Phenoxy acetic acids and phenyl propionic acids as PPAR delta agonists

ABSTRACT

Phenoxy acetic acids and phenyl propionic acids and their use in improving mitochondrial energy output in a subject are provided herein. The present compounds are activators of PPARδ and may be useful for treating conditions mediated by the same.

FIELD OF THE INVENTION

The present invention relates to novel compounds, to the use of thesecompounds as pharmaceutical compositions, to pharmaceutical compositionscomprising the compounds and to a method of treatment employing thesecompounds and compositions. The compounds are activators of peroxisomeproliferator-activated receptors (PPAR)-δ.

BACKGROUND OF THE INVENTION

Coronary artery disease (CAD) is the major cause of death in Type 2diabetic and metabolic syndrome patients (i.e. patients that fall withinthe ‘deadly quartet’ category of impaired glucose tolerance, insulinresistance, hypertriglyceridaemia and/or obesity).

The hypolipidaemic fibrates and antidiabetic thiazolidinedionesseparately display moderately effective triglyceride-lowering activitiesalthough they are neither potent nor efficacious enough to be a singletherapy of choice for the dyslipidaemia often observed in Type 2diabetic or metabolic syndrome patients. The thiazolidinediones alsopotently lower circulating glucose levels of Type 2 diabetic animalmodels and humans. However, the fibrate class of compounds are withoutbeneficial effects on glycaemia. Studies on the molecular actions ofthese compounds indicate that thiazolidinediones and fibrates exerttheir action by activating distinct transcription factors of theperoxisome proliferator activated receptor (PPAR) family, resulting inincreased and decreased expression of specific enzymes andapolipoproteins respectively, both key-players in regulation of plasmatriglyceride content.

PPARδ activation was initially reported not to be involved in modulationof glucose or triglyceride levels. (Berger et al., j. Biol. Chem., 1999,Vol 274, pp. 6718-6725). Later it has been shown that PPARδ activationleads to increased levels of HDL cholesterol in db/db mice (Leibowitz etal. FEBS letters 2000, 473, 333-336). Further, a PPARδ agonist whendosed to insulin-resistant middle-aged obese rhesus monkeys caused adramitic dose-dependent rise in serum HDL cholesterol while lowering thelevels of small dense LDL, fasting triglycerides and fasting insulin(Oliver et al. PNAS 2001, 98, 5306-5311). The same paper also showedthat PPARδ activation increased the reverse cholesterol transporterATP-binding cassette A1 and induced apolipoprotein A1-specificcholesterol efflux. The involvement of PPARδ in fatty acid oxidation inmuscles was further substantiated in PPARα knockout mice. Muoio et al.(J. Biol. Chem. 2002, 277, 26089-26097) showed that the high levels ofPPARδ in skeletal muscle can compensate for deficiency in PPARα. Inaddition to the effects on cholesterol homeostasis, PPARδ treatment wasobserved to lower plasma glucose and insulin and improve insulinsensitivity in diabetic ob/ob mice and high fat diet induced insulinresistant mice (PNAS 2003, 100, 15924-15929). Taken together theseobservations suggest that PPARδ activation is useful in the treatmentand prevention of Type 2 diabetes and cardiovascular diseases andconditions including atherosclerosis, hypertriglyceridemia, and mixeddyslipidaemia (WO 01/00603).

A number of PPARδ compounds have been reported to be useful in thetreatment of hyperglycemia, hyperlipidemia and hypercholesterolemia (WO02/59098, WO 01/603, WO 01/25181, WO 02/14291, WO 01/79197, WO 99/4815,WO 97/28149, WO 98/27974, WO 97/28115, WO 97/27857, WO 97/28137, WO97/27847 WO 2004093879, WO 2004092117, WO 2004080947, WO 2004080943, WO2004073606, WO 2004063166, WO 2004063165, WO 2003072100, WO 2004060871,WO 2004005253, WO 2003097607, WO 2003035603, WO 2004000315, WO2004000762, WO 2003074495, WO 2002070011, WO 2003084916, US 20040209936,WO 2003074050, WO 2003074051, WO 2003074052, JP 2003171275, WO2003033493, WO 2003016291, WO 2002076957, WO 2002046154, WO 2002014291,WO 2001079197, WO 2003024395, WO 2002059098, WO 2002062774, WO2002050048, WO 2002028434, WO 2001000603, WO 2001060807, WO 9728149, WO2001034200, WO 9904815, WO 200125226, WO 2005097098, WO 2005097762, andWO 2005097763.

Glucose lowering as a single approach does not overcome themacrovascular complications associated with Type 2 diabetes andmetabolic syndrome. Novel treatments of Type 2 diabetes and metabolicsyndrome must therefore aim at lowering both the overthypertriglyceridaemia associated with these syndromes as well asalleviation of hyperglycaemia. This indicate that research for compoundsdisplaying various degree of PPARδ activation should lead to thediscovery of efficacious triglyceride and/or cholesterol and/or glucoselowering drugs that have great potential in the treatment of diseasessuch as type 2 diabetes, dyslipidemia, syndrome X (including themetabolic syndrome, i.e. impaired glucose tolerance, insulin resistance,hypertrigyceridaemia and/or obesity), cardiovascular diseases (includingatherosclerosis) and hypercholesteremia.

Definitions

All references described herein are incorporated in there entirety byreference.

“Substituted” signifies that one or more hydrogen atoms are replaced bythe designated substituent. Only pharmaceutically stable compounds areintended to be covered.

When examples of definitions are provided, the definition is not meantto be limited to the specific examples.

The present invention includes all isotopes of atoms occurring in thepresent compounds. Isotopes include those atoms having the same atomicnumber but different mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium. Isotopesof carbon include C-13 and C-14.

When O or S is listed as a substituent, oxo and sulfo, respectively, itis intended that a carbon atom be replaced by either the O or S. Forexample if alkyl were substituted by O, then an ether would be formed.Preferably heteroatom-heteroatom bonds such as O—O, O—S, O—N, SS, andS—N are not formed.

The term “C₁₋₆-alkyl” as used herein, alone or in combination, representa linear or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms. Representative examples include, but are notlimited to methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.

The term “C₁₋₆-alkylcarbonyl as used herein, represents a “C₁₋₆-alkyl”group as defined above having the indicated number of carbon atomslinked through a carbonyl group.

Representative examples include, but are not limited to, methylcarbonyl,ethylcarbonyl, npropylcarbonyl, isopropylcarbonyl, butylcarbonyl,isobutylcarbonyl, sec-butylcarbonyl, tertbutylcarbonyl,n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl,tert-pentylcarbonyl, nhexylcarbonyl, isohexylcarbonyl and the like.

The term “C₁₋₆-alkylsulfonyl” as used herein refers to a monovalentsubstituent comprising a “C₁₋₆-alkyl” group as defined above linkedthrough a sulfonyl group. Representative examples include, but are notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl,neopentylsulfonyl, tert-pentylsulfonyl, n-hexylsulfonyl,isohexylsulfonyl and the like.

The term “C₁₋₆-alkylamido” as used herein, refers to an acyl grouplinked through an amino group; Representative examples include, but arenot limited to acetylamino, propionylamino, butyrylamino,isobutyrylamino, pivaloylamino, valerylamino and the like.

The term “C₃₋₆-cycloalkyl” as used herein, alone or in combination,represent a saturated monocyclic hydrocarbon group having the indicatednumber of carbon atoms. Representative examples include, but are notlimited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike.

The term “C₂₋₆-alkenyl” as used herein, represent an olefinicallyunsaturated branched or straight hydrocarbon group having from 2 to thespecified number of carbon atoms and at least one double bond.Representative examples include, but are not limited to, vinyl,1-propenyl, 2-propenyl, allyl, iso-propenyl, 1,3-butadienyl, 1-butenyl,hexenyl, pentenyl and the like.

The term “C₂₋₆-alkynyl” as used herein, represent an unsaturatedbranched or straight hydrocarbon group having from 2 to the specifiednumber of carbon atoms and at least one triple bond. Representativeexamples include, but are not limited to, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl and the like.

The term “C₄₋₆-alkenynyl” as used herein, represent an unsaturatedbranched or straight hydrocarbon group having from 4 to the specifiednumber of carbon atoms and both at least one double bond and at leastone triple bond. Representative examples include, but are not limitedto, 1-penten-4-ynyl, 3-penten-1-ynyl, 1,3-hexadiene-5-ynyl and the like.

The term “C₁₋₆-alkoxy” as used herein, alone or in combination, refersto a straight or branched configuration linked through an ether oxygenhaving its free valence bond from the ether oxygen. Examples of linearalkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy andthe like. Examples of branched alkoxy are isopropoxy, sec-butoxy,tert-butoxy, isopentyloxy, isohexyloxy and the like.

The term “C₃₋₆-cycloalkoxy” as used herein, alone or in combination,represent a saturated monocyclic hydrocarbon group having the indicatednumber of carbon atoms linked through an ether oxygen having its freevalence bond from the ether oxygen. Examples of cycloalkoxy groups arecyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and thelike.

The term “C₁₋₆-alkylthio” as used herein, alone or in combination,refers to a straight or branched monovalent substituent comprising a“C₁₋₆-alkyl” group as defined above linked through a divalent sulfuratom having its free valence bond from the sulfur atom and having 1 to 6carbon atoms. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, pentylthio and the like.

The term “C₃₋₆-cycloalkylthio” as used herein, alone or in combination,represent a saturated monocyclic hydrocarbon group having the indicatednumber of carbon atoms linked through a divalent sulfur atom having itsfree valence bond from the sulfur atom. Representative examples include,but are not limited to are cyclopropylthio, cyclobutylthio,cyclopentylthio, cyclohexylthio and the like.

The term “C₁₋₆-alkylsulfinyl” as used herein refers to a monovalentsubstituent comprising a straight or branched C₁₋₆-alkyl group linkedthrough a sulfinyl group (—S(═O)—); such as e.g. methylsulfinyl,ethylsulfinyl, isopropylsulfinyl, butylsulfinyl, pentylsulfinyl, and thelike.

The term “C₃₋₆-cycloalkylsulfinyl” as used herein refers to a monovalentsubstituent comprising a C₃₋₆-cycloalkyl group linked through a sulfinylgroup (—S(═O)—); such as e.g. cyclopropylsulfinyl, cyclobutylsulfinyl,cyclopentylsulfinyl, cyclohexylsulfinyl and the like.

The term “C₁₋₆-alkylamino” as used herein, alone or in combination,refers to a straight or branched monovalent substituent comprising a“C₁₋₆-alkyl” group as defined above linked through amino having a freevalence bond from the nitrogen atom. Representative examples include,but are not limited to, methylamino, ethylamino, propylamino,butylamino, pentylamino and the like.

The term “C₁₋₆-alkylaminocarbonyl” as used herein refers to a monovalentsubstituent comprising a C₁₋₆-monoalkylamino group linked through acarbonyl group such as e.g. methylaminocarbonyl, ethylaminocarbonyl,n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl,sec-butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl,n-pentylaminocarbonyl, 2-methylbutylaminocarbonyl,3-methylbutylaminocarbonyl, n-hexylaminocarbonyl,4-methylpentylaminocarbonyl, neopentylaminocarbonyl,n-hexylaminocarbonyl and 2-2-dimethylpropylaminocarbonyl and the like.

The term “C₃₋₆-cycloalkylamino” as used herein, alone or in combination,represent a saturated monocyclic hydrocarbon group having the indicatednumber of carbon atoms linked through amino having a free valence bondfrom the nitrogen atom. Representative examples include, but are notlimited to, cyclopropylamino, cyclobutylamino, cyclopentylamino,cyclohexylamino and the like.

The term “C₁₋₆-alkoxyC₁₋₆-alkyl” as used herein, alone or incombination, refers to a “C₁₋₆-alkyl” group as defined above whereto isattached a “C₁₋₆-alkoxy” group as defined above. Representative examplesinclude, but are not limited to, methoxymethyl, ethoxymethyl,methoxyethyl, ethoxyethyl and the like.

The term “aryl” as used herein is intended to include monocyclic,bicyclic or polycyclic carbocyclic aromatic rings. Representativeexamples are phenyl, naphthyl (e.g. naphth-1-yl, naphth-2-yl), anthryl(e.g. anthr-1-yl, anthr-9-yl), phenanthryl (e.g. phenanthr-1-yl,phenanthr-9-yl), and the like. Aryl is also intended to includemonocyclic, bicyclic or polycyclic carbocyclic aromatic ringssubstituted with carbocyclic aromatic rings. Representative examples arebiphenyl (e.g. biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl),phenylnaphthyl (e.g. 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and thelike. Aryl is also intended to include partially saturated bicyclic orpolycyclic carbocyclic rings with at least one unsaturated moiety (e.g.a benzo moiety). Representative examples are, indanyl (e.g. indan-1-yl,indan-5-yl), indenyl (e.g. inden-1-yl, inden-5-yl),1,2,3,4-tetrahydronaphthyl (e.g. 1,2,3,4-tetrahydronaphth-1-yl,1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl),1,2-dihydronaphthyl (e.g. 1,2-dihydronaphth-1-yl,1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g.fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is alsointended to include partially saturated bicyclic or polycycliccarbocyclic aromatic rings containing one or two bridges. Representativeexamples are, benzonorbornyl (e.g. benzonorborn-3-yl,benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronapthyl (e.g.1,4-ethano-1,2,3,4-tetrahydronapth-2-yl,1,4-ethano-1,2,3,4-tetrahydronapth-10-yl),and the like. Aryl is also intended to include partially saturatedbicyclic or polycyclic carbocyclic aromatic rings containing one or morespiro atoms. Representative examples arespiro[cyclopentane-1,1′-indane]-4-yl,spiro[cyclopentane-1,1′-indene]-4-yl,spiro[piperidine-4,1′-indane]-1-yl, spiro[piperidine-3,2′-indane]-1-yl,spiro[piperidine-4,2′-indane]-1-yl, spiro[piperidine-4,1′-indane]-3′-yl,spiro[pyrrolidine-3,2′-indane]-1-yl,spiro[pyrrolidine-3,1′-(3′,4′-dihydronaphthalene)]-1-yl,spiro[piperidine-3,1′-(3′,4′-dihydronaphthalene)]-1 yl,spiro[piperidine-4,1′-(3′,4′-dihydronaphthalene)]-1-yl,spiro[imidazolidine-4,2′-indane]-1-yl,spiro[piperidine-4,1′-indene]-1-yl, and the like. Other examples of“aryl” are phenyl, naphthyl, anthracenyl, phenanthrenyl, azulenyl,fluorenyl, indenyl and pentalenyl.

The term “arylene” as used herein refers to divalent aromatic monocyclicor a divalent aromatic fused bi- or tricyclic hydrocarbon group.Representative examples include, but are not limited to, phenylene,naphthylene and the like.

The term “arylcarbonyl” as used herein refers to the radicalaryl-C(═O)—. Representative examples are benzoyl, naphthylcarbonyl,4-phenylbenzoyl, anthrylcarbonyl, phenanthrylcarbonyl, azulenylcarbonyland the like.

The term “heteroarylcarbonyl” as used herein refers to the radicalheteroaryl-C(═O)—.

Representative examples are pyridinylcarbonyl (e.g.pyridin-2-ylcarbonyl, pyridin-4-ylcarbonyl), quinolinylcarbonyl (e.g.2-(quinolin-2-yl)carbonyl, 1-(quinolin-2-yl)carbonyl),imidazolylcarbonyl (e.g. imidazol-2-ylcarbonyl, imidazol-5-ylcarbonyl),and the like.

The term “arylsulfonyl” as used herein refers to an “aryl” group asdefined above linked through a sulfonyl group. Representative examplesinclude, but are not limited to, phenylsulfonyl, naphthylsulfonyl,anthracenylsulfonyl, phenanthrenylsulfonyl, azulenylsulfonyl, and thelike.

The term “arylamido” as used herein refers to an arylcarbonyl grouplinked through an amino group. Representative examples include, but arenot limited to phenylcarbonylamino, naphthylcarbonylamino,anthracenylcarbonylamino, phenanthrenylcarbonylamino,azulenylcarbonylamino and the like.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “perhalomethyl” means trifluoromethyl, trichloromethyl,tribromomethyl or triiodomethyl.

The term “perhalomethoxy” means trifluoromethoxy, trichloromethoxy,tribromomethoxy or triiodomethoxy.

The term “C₁₋₆-dialkylamino” as used herein refers to an amino groupwherein the two hydrogen atoms independently are substituted with astraight or branched, saturated hydrocarbon chain having the indicatednumber of carbon atoms. Representative examples include, but are notlimited to, N,N-dimethylamino, N-ethyl-N-methylamino, N,N-diethylamino,N,N-dipropylamino (e.g. N,N-(prop-1-yl)₂amino, N,N-(prop-2-yl)₂amino,N,N-(prop-3-yl)₂-amino), N-(but-1-yl)-N-methylamino,N,N-(pent-1-yl)₂amino, and the like.

The term “acyl” as used herein refers to a monovalent substituentcomprising a “C₁₋₆-alkyl” group as defined above linked through acarbonyl group. Representative examples include, but are not limited to,acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.

The term “heteroaryl” as used herein, alone or in combination, refers toa monovalent substituent comprising a 5-7 membered monocyclic aromaticsystem or a 8-10 membered bicyclic aromatic system containing one ormore heteroatoms selected from nitrogen, oxygen and sulphur. Examples of“heteroaryl” are pyrrolyl (e.g. pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl),furanyl (e.g. furan-2-yl, furan-3-yl), thienyl (e.g. thien-2-yl,thien-3-yl), oxazolyl (e.g. oxazol-2-yl, oxazol-4-yl, oxazol-5-yl),thiazolyl (e.g. thiazol-2-yl, thiazol-4-yl, thiazol-5-yl), imidazolyl(e.g. imidazol-2-yl, imidazol-4-yl, imidazol-5-yl), pyrazolyl (e.g.pyrazol-1-yl, pyrazol-3-yl, pyrazol-5-yl), isoxazolyl (e.g.isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl), isothiazolyl (e.g.isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl), 1,2,3-triazolyl(e.g. 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl),1,2,4-triazolyl (e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl,1,2,4-triazol-5-yl), 1,2,3-oxadiazolyl (e.g. 1,2,3-oxadiazol-4-yl,1,2,3-oxadiazol-5-yl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl), 1,2,5-oxadiazolyl (e.g. 1,2,5-oxadiazol-3-yl,1,2,5-oxadiazol-4-yl), 1,3,4-oxadiazolyl (e.g. 1,3,4-oxadiazol-2-yl,1,3,4-oxadiazol-5-yl), 1,2,3-thiadiazolyl (e.g. 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl), 1,2,4-thiadiazolyl (e.g. 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl), 1,2,5-thiadiazolyl (e.g. 1,2,5-thiadiazol-3-yl,1,2,5-thiadiazol-4-yl), 1,3,4-thiadiazolyl (e.g. 1,3,4-thiadiazol-2-yl,1,3,4-thiadiazol-5-yl), tetrazolyl (e.g. tetrazol-1-yl, tetrazol-5-yl),pyranyl (e.g. pyran-2-yl), pyridinyl (e.g. pyridine-2-yl, pyridine-3-yl,pyridine-4-yl), pyridazinyl (e.g. pyridazin-2-yl, pyridazin-3-yl),pyrimidinyl (e.g. pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl),pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,thiadiazinyl, azepinyl, azecinyl, indolyl (e.g. indol-1-yl, indol-2-yl,indol-3-yl, indol-5-yl), isoindolyl, benzofuranyl (e.g.benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-5-yl,benzo[c]furan-2-yl, benzo[c]furan-3-yl, benzo[c]furan-5-yl),benzothienyl (e.g. benzo[b]thien-2-yl, benzo[b]thien-3-yl,benzo[b]thien-5-yl, benzo[c]thien-2-yl, benzo[c]thien-3-yl,benzo[c]thien-5-yl), indazolyl (e.g. indazol-1-yl, indazol-3-yl,indazol-5-yl), indolizinyl (e.g. indolizin-1-yl, indolizin-3-yl),benzopyranyl (e.g. benzo[b]pyran-3-yl, benzo[b]pyran-6-yl,benzo[c]-pyran-1-yl, benzo[c]pyran-7-yl), benzimidazolyl (e.g.benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzothiazolyl(e.g. benzothiazol-2-yl, benzothiazol-5-yl), benzisothiazolyl,benzoxazolyl, benzisoxazolyl, benzoxazinyl, benzotriazolyl,naphthyridinyl (e.g. 1,8-naphthyridin-2-yl, 1,7-naphthyridin-2-yl,1,6-naphthyridin-2-yl), phthalazinyl (e.g. phthalazin-1-yl,phthalazin-5-yl), pteridinyl, purinyl (e.g. purin-2-yl, purin-6-yl,purin-7-yl, purin-8-yl, purin-9-yl), quinazolinyl (e.g. quinazolin-2-yl,quinazolin-4-yl, quinazolin-6-yl), cinnolinyl, quinoliny (e.g.quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-6-yl),isoquinolinyl (e.g. isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl), quinoxalinyl (e.g. quinoxalin-2-yl, quinoxalin-5-yl),pyrrolopyridinyl (e.g. pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl), furopyridinyl (e.g. furo[2,3-b]pyridinyl,furo[2,3-c]pyridinyl, furo[3,2-c]pyridinyl), thienopyridinyl (e.g.thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-c]pyridinyl),imidazopyridinyl (e.g. imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,imidazo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl), imidazopyrimidinyl(e.g. imidazo[1,2-a]pyrimidinyl, imidazo[3,4-a]pyrimidinyl),pyrazolopyridinyl (e.g. pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[1,5-a]pyridinyl), pyrazolopyrimidinyl(e.g. pyrazolo[1,5-a]pyrimidinyl, pyrazolo[3,4-d]pyrimidinyl),thiazolopyridinyl (e.g. thiazolo[3,2-d]pyridinyl), thiazolopyrimidinyl(e.g. thiazolo[5,4-d]pyrimidinyl), imdazothiazolyl (e.g.imidazo[2,1-b]thiazolyl), triazolopyridinyl (e.g.triazolo[4,5-b]pyridinyl), triazolopyrimidinyl (e.g. 8-azapurinyl),carbazolyl (e.g. carbazol-2-yl, carbazol-3-yl, carbazol-9-yl),phenoxazinyl (e.g. phenoxazin-10-yl), phenazinyl (e.g. phenazin-5-yl),acridinyl (e.g. acridin-9-yl, acridin-10-yl), phenolthiazinyl (e.g.phenothiazin-10-yl), carbolinyl (e.g. pyrido[3,4-b]indol-1-yl,pyrido[3,4-b]indol-3-yl), phenanthrolinyl (e.g. phenanthrolin-5-yl),pyrrolinyl, pyrazolinyl, imidazolinyl (e.g. 4,5-dihydroimidazol-2-yl,4,5-dihydroimidazol-1-yl), indolinyl (e.g. 2,3-dihydroindol-1-yl,2,3-dihydroindol-5-yl), dihydrobenzofuranyl (e.g.2,3-dihydrobenzo[b]furan-2-yl, 2,3-dihydrobenzo[b]furan-4-yl),dihydrobenzothienyl (e.g. 2,3-dihydrobenzo[b]thien-2-yl,2,3-dihydrobenzo[b]thien-5-yl), 4,5,6,7-tetrahydrobenzo[b]furan-5-yl),dihydrobenzopyranyl (e.g. 3,4-dihydrobenzo[b]pyran-3-yl,3,4-dihydrobenzo[b]pyran-6-yl, 3,4-dihydrobenzo[c]pyran-1-yl,dihydrobenzo[c]pyran-7-yl), oxazolinyl (e.g. 4,5-dihydrooxazol-2-yl,4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl), isoxazolinyl,oxazepinyl, tetrahydroindazolyl (e.g. 4,5,6,7-tetrahydroindazol-1-yl,4,5,6,7-tetrahydroindazol-3-yl, 4,5,6,7-tetrahydroindazol-4-yl,4,5,6,7-tetrahydroindazol-6-yl), tetrahydrobenzimidazolyl (e.g.4,5,6,7-tetrahydrobenzimidazol-1-yl,4,5,6,7-tetrahydrobenzimidazol-5-yl), tetrahydroimidazo[4,5-c]pyridyl(e.g. 4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-1-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-5-yl,4,5,6,7-tetrahydroimidazo[4,5-c]pyrid-6-yl), tetrahydroquinolinyl (e.g.1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolinyl),tetrahydroisoquinolinyl (e.g. 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinoxalinyl (e.g.1,2,3,4-tetrahydroquinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl),spiro[isoquinoline-3,1′-cyclohexan]-1-yl,spiro[piperidine-4,1′-benzo[c]thiophen]-1-yl,spiro[piperidine-4,1′-benzo[c]furan]-1-yl,spiro[piperidine-4,3′-benzo[b]furan]-1-yl,spiro[piperidine-4,3′-coumarin]-1-yl.

Other examples of “heteroaryl” are furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinnyl, indolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzoxazolyl, tetrazolyl, carbazolylpteridinyl and purinyl.

The term “heteroarylene” as used herein, alone or in combination, refersto divalent 5-7 membered monocyclic aromatic system or a 8-10 memberedbicyclic aromatic system containing one or more heteroatoms selectedfrom nitrogen, oxygen and sulfur, e.g. furylene, thienylene,pyrrolylene, imidazolylene, pyrazolylene, triazolylene, pyridylene,pyrazinylene, pyrimidinylene, pyridazinylene, isothiazolylene,isoxazolylene, oxazolylene, oxadiazolylene, thiadiazolylene,quinolylene, isoquinolylene, quinazolinylene, quinoxalinnylene,indolylene, benzimidazolylene, benzofuranylene, benzothienylene,pteridinylene and purinylene and the like.

The term “heteroaryloxy” as used herein, alone or in combination, refersto a heteroaryl as defined herein linked to an oxygen atom having itsfree valence bond from the oxygen atom e.g. pyrrolyloxy, imidazolyloxy,pyrazolyloxy, triazolyloxy, pyrazinyloxy, pyrimidinyloxy,pyridazinyloxy, isothiazolyloxy, isoxazolyloxy, oxazolyloxy,oxadiazolyloxy, thiadiazolyloxy, quinolinyloxy, isoquinolinyloxy,quinazolinyloxy, quinoxalinyloxy, indoltloxy, benzimidazolyloxy,benzofuranyloxy, pteridinyloxy and purinyloxy and the like.

The term “aralkyl” as used herein refers to a straight or branchedsaturated carbon chain containing from 1 to 6 carbons substituted withan aromatic carbohydride. Representative examples include, but are notlimited to, benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl,2-(1-naphthyl)ethyl and the like.

The term “aryloxy” as used herein refers to phenoxy, 1-naphthyloxy,2-naphthyloxy and the like.

The term “aralkoxy” as used herein refers to a C₁₋₆-alkoxy groupsubstituted with an aromatic carbohydride, such as benzyloxy,phenethoxy, 3-phenylpropoxy, 1-naphthylmethoxy, 2-(1-naphtyl)ethoxy andthe like.

The term “heteroaralkyl” as used herein refers to a straight or branchedsaturated carbon chain containing from 1 to 6 carbons substituted with aheteroaryl group; such as (2-furyl)methyl, (3-furyl)methyl,(2-thienyl)methyl, (3-thienyl)methyl, (2-pyridyl)methyl,1-methyl-1-(2-pyrimidyl)ethyl and the like.

The term “heteroaralkoxy” as used herein refers to a heteroarylalkyl asdefined herein linked to an oxygen atom having its free valence bondfrom the oxygen atom.

Representative examples include, but are not limited to,(2-furyl)methyl, (3-furyl)methyl, (2-thienyl)methyl, (3-thienyl)methyl,(2-pyridyl)methyl, 1-methyl-1-(2-pyrimidyl)ethyl linked to oxygen, andthe like.

The term “arylthio” as used herein, alone or in combination, refers toan aryl group linked through a divalent sulfur atom having its freevalence bond from the sulfur atom, the aryl group optionally being mono-or polysubstituted with C₁₋₆-alkyl, halogen, hydroxy or C₁₋₆-alkoxy.Representative examples include, but are not limited to, phenylthio,(4-methylphenyl)-thio, (2-chlorophenyl)thio and the like.

The term “Heterocyclyl” or “heterocycle” signifies a mono-, bi-, ortricyclic ring consisting of carbon atoms and from one to threeheteroatom, wherein the heteroatom is selected from oxygen, nitrogen,and sulphur. If sulphur is present, then it can be S, S(O), or S(O)₂. Ifnitrogen is present, then it can be N, NH, substituted N, or N-oxide.The heterocycle is a saturated or partially saturated ring. From 0-2 CH₂groups of the heterocycle can be replaced by C(O). The heterocycle canbe attached via a carbon or nitrogen atom, unless linking the nitrogenatom would lead to a quaternary nitrogen. If the heterocycle isbicyclic, then one or both of the rings may have a heteroatom(s)present. If the heterocycle is tricyclic, then one, two, or all three ofthe rings may have a heteroatom(s) present. Examples of “heterocycle”are aziridinyl (e.g. aziridin-1-yl), azetidinyl (e.g. azetidin-1-yl,azetidin-3-yl), oxetanyl, pyrrolidinyl (e.g. pyrrolidin-1-yl,pyrrolidin-2-yl, pyrrolidin-3-yl), imidazolidinyl (e.g.imidazolidin-1-yl, imidazolidin-2-yl, imidazolidin-4-yl), oxazolidinyl(e.g. oxazolidin-2-yl, oxazolidin-3-yl, oxazolidin-4-yl), thiazolidinyl(e.g. thiazolidin-2-yl, thiazolidin-3-yl, thiazolidin-4-yl),isothiazolidinyl, piperidinyl (e.g. piperidin-1-yl, piperidin-2-yl,piperidin-3-yl, piperidin-4-yl), homopiperidinyl (e.g.homopiperidin-1-yl, homopiperidin-2-yl, homopiperidin-3-yl,homopiperidin-4-yl), piperazinyl (e.g. piperazin-1-yl, piperazin-2-yl),morpholinyl (e.g. morpholin-2-yl, morpholin-3-yl, morpholin-4-yl),thiomorpholinyl (e.g. thiomorpholin-2-yl, thiomorpholin-3-yl,thiomorpholin-4-yl), 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl, tetrahydrofuran-3-yl),tetrahydrothienyl, tetrahydro-1,1-dioxothienyl, tetrahydropyranyl (e.g.2-tetrahydropyranyl), tetrahydrothiopyranyl (e.g.2-tetrahydrothiopyranyl), 1,4-dioxanyl, 1,3-dioxanyl, octahydroindolyl(e.g. octahydroindol-1-yl, octahydroindol-2-yl, octahydroindol-3-yl,octahydroindol-5-yl), decahydroquinolinyl (e.g. decahydroquinolin-1-yl,decahydroquinolin-2-yl, decahydroquinolin-3-yl, decahydroquinolin-4-yl,decahydroquinolin-6-yl), decahydroquinoxalinyl (e.g.decahydroquinoxalin-1-yl, decahydroquinoxalin-2-yl,decahydroquinoxalin-6-yl), 3-azabicyclo[3.2.2]nonyl,2-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl,2,5-diazabicyclo[2.2.1]heptyl, atropinyl, tropinyl, quinuclidinyl,1,4-diazabicyclo[2.2.2]octanyl, 1,4-dioxaspiro[4.5]decanyl (e.g.1,4-dioxaspiro[4.5]decan-2-yl, 1,4-dioxaspiro[4.5]decan-7-yl),1,4-dioxa-8-azaspiro[4.5]decanyl (e.g.1,4-dioxa-8-azaspiro[4.5]decan-2-yl,1,4-dioxa-8-azaspiro[4.5]decan-8-yl), 8-azaspiro[4.5]decanyl (e.g.8-azaspiro[4.5]decan-1-yl, 8-azaspiro[4.5]decan-8-yl),2-azaspiro[5.5]undecanyl (e.g. 2-azaspiro[5.5]undecan-2-yl),2,8-diazaspiro[4.5]decanyl (e.g. 2,8-diazaspiro[4.5]decan-2-yl,2,8-diazaspiro[4.5]decan-8-yl), 2,8-diazaspiro[5.5]undecanyl (e.g.2,8-diazaspiro[5.5]undecan-2-yl), 1,3,8-triazaspiro[4.5]decanyl (e.g.1,3,8-triazaspiro[4.5]decan-1-yl, 1,3,8-triazaspiro[4.5]decan-3-yl, and1,3,8-triazaspiro[4.5]decan-8-yl). Other examples of “heterocycle” arepyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, imidzolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, oxazolidinyl, oxazoline, isoxazolidinyl,isoxazoline, thioxazolidinyl, thioxazoline, isothioxazolidinyl,isothioxazoline, triazolidinyl, triazolinyl, tetrazolidinyl,tetrazolinyl, tetrahydropyranyl, dihydropyranyl, pyran, piperidinyl,piperazinyl, homopiperazinyl, morpholino, thiomorpholino, and1,1-dioxothiomorpholino.

The term “five to eight member ring” as used herein refers to asaturated or unsaturated, substituted or unsubstituted hydrocarbon chainor hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein thecarbon atom in Ar, to which they are attached, and the adjacent carbonatom form a five to eight member ring.

Certain of the above defined terms may occur more than once in thestructural formulae, and upon such occurrence each term shall be definedindependently of the other.

The term “optionally substituted” as used herein means that the groupsin question are either unsubstituted or substituted with one or more ofthe substituents specified. When the groups in question are substitutedwith more than one substituent the substituents may be the same ordifferent.

The term “prodrug” as used herein includes biohydrolyzable amides andbiohydrolyzable esters and also encompasses a) compounds in which thebiohydrolyzable functionality in such a prodrug is encompassed in thecompound according to the present invention, and b) compounds which maybe oxidized or reduced biologically at a given functional group to yielddrug substances according to the present invention. Examples of thesefunctional groups include 1,4-dihydropyridine,N-alkylcarbonyl-1,4-dihydropyridine, 1,4-cyclohexadiene, tert-butyl, andthe like.

The term “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, e.g.,arresting or slowing its development; and/or (c) relieving thedisease-state, e.g., causing regression of the disease state itself orsome symptom of the disease state.

The term “pharmaceutically acceptable” is defined as being suitable foradministration to humans without adverse events.

The term “therapeutically effective amount” is intended to include anamount of a compound of the present invention that is effective whenadministered alone or in combination to activate glucokinase.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the general formula (I):

wherein

is a double bond, with either E or Z substitution;X₁ is heterocyclyl, aryl or heteroaryl each of which is optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy, cyano, amino, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        aralkyl, heteroaryl, heteroaralkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy or halogen; or        wherein X₁ is heterocyclyl-C₁₋₆-alkyl, aralkyl or heteroaralkyl        each of which is optionally substituted with one or more        substituents selected from    -   halogen, hydroxy, cyano, amino, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy, carboxy or halogen; or        X₁ is C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, carbamoyl or        C₃₋₆-cycloalkyl-C₁₋₆-alkyl each of which is optionally        substituted with one or more substituents selected from    -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryloxy, heteroaryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl-carbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cyCloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-cycloalkoxycarbonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxycarbonyl,        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylamido,        C₃₋₆-cycloalkylamido, C₃₋₆-cycloalkyl-C₁₋₆-alkylamido,        arylamido, C₁₋₆-alkylaminocarbonyl,        C₃₋₆-cycloalkylaminocarbonyl,        C₃₋₆-Cycloalkyl-C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl,        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino,        C₃₋₆-Cycloalkyl-C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino,        di-(C₃₋₆-cycloalkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino each of which is optionally        substituted with one or more of halogen, C₁₋₆-alkyl, cyano,        hydroxy, hydroxy-C₁₋₆-alkyl, acetyl or oxo;        X₂ is arylene or heteroarylene each of which is optionally        substituted with one or more substituents selected from    -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more halogens; and        X₃ is aryl or heteroaryl each of which is optionally substituted        with one or more substituents selected from    -   halogen, perhalomethyl, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        perhalomethylthio, C₁₋₆-alkylsulfinyl, C₃₋₆-cycloalkylsulfinyl,        C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl, heteroaryl or C₃₋₆-cycloalkylamino each of which is        optionally substituted with one or more C₁₋₆-alkyl or halogens;        and        Ar is arylene which is optionally substituted with one or more        substituents selected from    -   halogen, hydroxy or cyano; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        heteroaryl, aralkyl, heteroaralkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio or C₃₋₆-cycloalkylthio each of which is        optionally substituted with one or more halogens; or    -   two of the substituents when placed in adjacent positions        together with the atoms to which they are attached may form a        five to eight member ring; and        Y₁ is O or S; and        Y₂ is O, S or CH₂; and        Z is —(CH₂)_(n)— wherein n is 1, 2 or 3; and        R₁ is hydrogen, halogen or a substituent selected from    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        aralkyl, heteroaralkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, aryloxy,        aralkoxy, heteroaralkoxy, C₁₋₆-alkylthio, arylthio or        C₃₋₆-cycloalkylthio each of which is optionally substituted with        one or more halogens; and        R₂ is hydrogen, C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, C₄₋₆-alkenynyl or aryl; or        a pharmaceutically acceptable salt thereof, or a        pharmaceutically acceptable solvate thereof, or any tautomeric        forms, stereoisomers, mixture of stereoisomers including a        racemic mixture, or polymorphs.

In another embodiment, the present invention relates to compounds of thegeneral formula (I) wherein X₁ is heterocyclyl, aryl or heteroaryl eachof which is optionally substituted with one or more substituentsselected from

-   -   halogen, hydroxy, cyano, amino, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        aralkyl, heteroaryl, heteroaralkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy or halogen; or        wherein X₁ is heterocyclyl-C₁₋₆-alkyl, aralkyl or heteroaralkyl        each of which is optionally substituted with one or more        substituents selected from    -   halogen, hydroxy, cyano, amino, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy, carboxy or halogen; or        X₁ is C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, carbamoyl or        C₃₋₆-cycloalkyl-C₁₋₆-alkyl each of which is optionally        substituted with one or more substituents selected from    -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryloxy, heteroaryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylcarbonyl, C₃₋₆-Cycloalkylcarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl-carbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-cycloalkoxycarbonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxycarbonyl,        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylamido,        C₃₋₆-cycloalkylamido, C₃₋₆-cycloalkyl-C₁₋₆-alkylamido,        arylamido, C₁₋₆-alkylaminocarbonyl,        C₃₋₆-cyCloalkylaminocarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl,        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino,        C₃₋₆-cycloalkyl-C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino,        di-(C₃₋₆-cycloalkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino each of which is optionally        substituted with one or more of halogen, C₁₋₆-alkyl, cyano,        hydroxy, hydroxy-C₁₋₆-alkyl, acetyl or oxo.

In another embodiment, the present invention relates to compounds of thegeneral formula (I), wherein X₁ is aryl or heteroaryl each of which isoptionally substituted with one or more substituents selected from

-   -   halogen, hydroxy, cyano, amino, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl,        aralkyl, heteroaryl, heteroaralkyl, C₁₋₆-alkoxy,        C₃₋₆-cycloalkoxy, aryloxy, aralkoxy, heteroaralkoxy,        C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy or halogen; or        X₁ is C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, carbamoyl or        C₃₋₆-cycloalkyl-C₁₋₆-alkyl each of which is optionally        substituted with one or more substituents selected from    -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryloxy, heteroaryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio,arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl-carbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-cycloalkoxycarbonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxycarbonyl,        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylamido,        C₃₋₆-cycloalkylamido, C₃₋₆-cycloalkyl-C₁₋₆-alkylamido,        arylamido, C₁₋₆-alkylaminocarbonyl,        C₃₋₆-cycloalkylaminocarbonyl,        C₃₋₆-Cycloalkyl-C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl,        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino,        C₃₋₆-Cycloalkyl-C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino,        di-(C₃₋₆-cycloalkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino each of which is optionally        substituted with one or more of halogen, C₁₋₆-alkyl, cyano,        hydroxy, hydroxy-C₁₋₆-alkyl, acetyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl optionally substituted withone or more substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, aryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkyl,amino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl, which is optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, arylthio,        C₃₋₆-cycloalkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl, which is optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, C₁₋₆-alkoxy,        C₁₋₆-alkylsulfonyl or arylsulfonyl, each of which is optionally        substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl, which is optionallysubstituted with one or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, aryl, or C₁₋₆-alkylsulfonyl, each of which is        optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aryl optionally substituted with one ormore substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        C₁₋₆-alkoxy, C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aryl optionally substituted with one ormore substituents selected from

-   -   halogen or oxo; or    -   C₁₋₆-alkyl, aryl, C₁₋₆-alkoxy or C₁₋₆-alkylsulfonyl each of        which is optionally substituted with one or more of hydroxy or        halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aryl optionally substituted with one ormore substituents selected from

-   -   halogen; or    -   C₁₋₆-alkyl optionally substituted with hydroxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aryl substituted with C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl optionally substituted with one ormore substituents selected from

-   -   halogen or oxo; or    -   C₁₋₆-alkyl, aryl, C₁₋₆-alkoxy or C₁₋₆-alkylsulfonyl each of        which is optionally substituted with one or more of hydroxy or        halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl optionally substituted with one ormore substituents selected from

-   -   halogen; or    -   C₁₋₆-alkyl optionally substituted with hydroxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl optionally substituted withtrifluoromethyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl optionally substituted with one ormore halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl optionally substituted with one ormore of methyl or ethyl, each of which is substituted with hydroxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl substituted with one or more ofmethyl or ethyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is phenyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        C₁₋₆-alkoxy, C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino each of which is optionally substituted        with one or more of hydroxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen or oxo; or    -   C₁₋₆-alkyl, aryl, C₁₋₆-alkoxy or C₁₋₆-alkylsulfonyl each of        which is optionally substituted with one or more of hydroxy or        halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen or oxo; or    -   C₁₋₆-alkyl or C₁₋₆-alkoxy each of which is optionally        substituted with one or more of hydroxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is pyridyl optionally substituted with one ormore of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is pyridyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is benzothienyl optionally substituted withone or more of oxo and C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is thienyl optionally substituted with one ormore of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, aryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkyl,amino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, arylthio,        C₃₋₆-cycloalkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, C₁₋₆-alkoxy,        C₁₋₆-alkylsulfonyl or arylsulfonyl, each of which is optionally        substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heterocyclyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, aryl, or C₁₋₆-alkylsulfonyl, each of which is        optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted with one ormore substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        aryloxy, aralkoxy, heteroaralkoxy, C₁₋₆-alkylthio, arylthio,        C₃₋₆-cycloalkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkyl,amino, each of which is optionally substituted        with one or more of carboxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted with one ormore substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        arylthio, C₃₋₆-cycloalkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino, each of which is optionally substituted        with one or more of carboxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted with one ormore substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, C₁₋₆-alkoxy,        C₁₋₆-alkylsulfonyl or arylsulfonyl, each of which is optionally        substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted with one ormore substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, aryl, or C₁₋₆-alkylsulfonyl, each of which is        optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted withheterocyclyl, which is optionally substituted with one or more ofcarboxy or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is aralkyl optionally substituted withpiperidinyl optionally substituted with carboxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaralkyl optionally substituted withone or more substituents selected from

-   -   halogen, hydroxy, oxo or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, aryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, arylthio, C₃₋₆-cycloalkylthio,        C₁₋₆-alkylcarbonyl, arylcarbonyl, C₁₋₆-alkylsulfonyl,        arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkyl,amino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaralkyl optionally substituted withone or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, arylthio,        C₃₋₆-cycloalkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, C₁₋₆-alkylamido, arylamido,        C₁₋₆-alkylaminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino or        C₃₋₆-cycloalkylamino, each of which is optionally substituted        with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaralkyl optionally substituted withone or more substituents selected from

-   -   halogen, hydroxy or oxo; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, aryl, aralkyl, C₁₋₆-alkoxy,        C₁₋₆-alkylsulfonyl or arylsulfonyl, each of which is optionally        substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is heteroaralkyl optionally substituted withone or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, aryl, or C₁₋₆-alkylsulfonyl, each of which is        optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl, aryl, aralkyl, heteroaryl,        heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryloxy, heteroaryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl-carbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-cycloalkoxycarbonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxycarbonyl,        aminoC₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylamido,        C₃₋₆-cycloalkylamido, C₃₋₆-cycloalkyl-C₁₋₆-alkylamido,        arylamido, C₁₋₆-alkylaminocarbonyl,        C₃₋₆-cycloalkylaminocarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl,        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino,        C₃₋₆-cycloalkyl-C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino,        di-(C₃₋₆-cycloalkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl, acetyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen, hydroxy, cyano, amino or carboxy; or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl, C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy,        C₃₋₆-cycloalkyl-C₁₋₆-alkoxy, aryloxy, heteroaryloxy, aralkoxy,        heteroaralkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, heteroaryl-C₁₋₆-alkylthio,        C₁₋₆-alkylcarbonyl, C₃₋₆-cycloalkylcarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkyl-carbonyl, arylcarbonyl,        heteroarylcarbonyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl,        heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkoxycarbonyl,        C₃₋₆-cycloalkoxycarbonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkoxycarbonyl,        amino-C₁₋₆-alkyl, C₁₋₆-alkylamino-C₁₋₆-alkyl,        di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl, C₁₋₆-alkylamido,        C₃₋₆-cycloalkylamido, C₃₋₆-cycloalkyl-C₁₋₆-alkylamido,        arylamido, C₁₋₆-alkylaminocarbonyl,        C₃₋₆-cycloalkylaminocarbonyl,        C₃₋₆-cycloalkyl-C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl,        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino,        C₃₋₆-cycloalkyl-C₁₋₆-alkylamino, di-(C₁₋₆-alkyl)amino,        di-(C₃₋₆-cycloalkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl, acetyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heterocyclyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cyCloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from C₁₋₆-alkyl, aryl, heterocyclyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxyC₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from aryl, aralkyl, heteroaryl,heteroaralkyl, heterocyclyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,C₃₋₆-Cycloalkylthio, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio,heteroarylthio, aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,di(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, cyano, hydroxy,hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from aryl, heteroaryl, heterocyclyl,C₃₋₆-cycloalkylthio, C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio,heteroarylthio, aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,C₁₋₆-alkylsulfonyl, arylsulfonyl, C₃₋₆-cycloalkylamino, ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, cyano, hydroxy,hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more substituents selected from C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cyCloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted witharyl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, each of which isoptionally substituted with one or more of halogen, C₁₋₆-alkyl, hydroxyor hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with aryl optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with aralkyloptionally substituted with one or more of halogen, C₁₋₆-alkyl, hydroxyor hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with heteroaryloptionally substituted with one or more of halogen, C₁₋₆-alkyl, hydroxyor hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with heteroaralkyloptionally substituted with one or more of halogen, C₁₋₆-alkyl, hydroxyor hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with heterocyclyl,optionally substituted with one or more of halogen, C₁₋₆-alkyl, hydroxyor hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted withheteroaryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with pyrazolyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with pyridyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with thienyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of heterocyclyl optionally substituted with one or moreC₁₋₆-alkyl, hydroxy or hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of morpholinyl, piperazinyl, piperidinyl or pyrrolidinyl, eachof which is optionally substituted with one or more of C₁₋₆-alkyl,hydroxy or hydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of morpholino, piperazino, piperidino or pyrrolidino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl substituted with morpholino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of C₁₋₆-alkylsulfonyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted with oneor more of C₁₋₆-alkylthio.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted withC₁₋₆-alkylamino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted withC₁₋₆-dialkylamino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted withdi-(C₁₋₆-alkyl)amino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₁₋₆-alkyl optionally substituted withdi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₃₋₆-cycloalkyl optionally substituted withone or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₃₋₆-cycloalkyl optionally substituted withone or more substituents selected from C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₂₋₆-alkenyl optionally substituted withone or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₂₋₆-alkenyl optionally substituted withone or more substituents selected from C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is carbamoyl optionally substituted with oneor more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is carbamoyl optionally substituted with oneor more substituents selected from C₁₋₆-alkyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cyCloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₃₋₆-cycloalkyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from

-   -   halogen or hydroxy; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,        C₃₋₆-cycloalkyl-C₁₋₆-alkylthio, arylthio, heteroarylthio,        aryl-C₁₋₆-alkylthio, C₁₋₆-alkylcarbonyl, arylcarbonyl,        C₁₋₆-alkylsulfonyl, arylsulfonyl, amino-C₁₋₆-alkyl,        C₁₋₆-alkylamino-C₁₋₆-alkyl, di-(C₁₋₆-alkyl)amino-C₁₋₆-alkyl,        C₁₋₆-alkylamido, arylamido, C₁₋₆-alkylaminocarbonyl,        di-(C₁₋₆-alkyl)aminocarbonyl, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino or        di-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is        optionally substituted with one or more of halogen, C₁₋₆-alkyl,        cyano, hydroxy, hydroxy-C₁₋₆-alkyl or oxo.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₁ is C₃₋₆-cycloalkyl-C₁₋₆-alkyl optionallysubstituted with one or more substituents selected from C₁₋₆-alkyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylthio, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,C₃₋₆-cycloalkylamino, di-(C₁₋₆-alkyl)amino ordi-(C₃₋₆-cycloalkyl-C₁₋₆-alkyl)amino, each of which is optionallysubstituted with one or more of halogen, C₁₋₆-alkyl, hydroxy orhydroxy-C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is arylene optionally substituted with one ormore substituents selected from

-   -   halogen or    -   C₁₋₆-alkyl optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is arylene optionally substituted with one ormore halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is phenylene optionally substituted with oneor more substituents selected from

-   -   halogen or    -   C₁₋₆-alkyl optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is phenylene optionally substituted with oneor more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is phenylene optionally substituted with oneor more of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is phenylene.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is heteroarylene optionally substituted withone or more substituents selected from

-   -   halogen or    -   C₁₋₆-alkyl optionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is heteroarylene optionally substituted withone or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₂ is heteroarylene.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with one or more substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, C₃₋₆-Cycloalkyl-C₁₋₆-alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl or heteroaryl, each of which is optionally substituted with        one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with one or more substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, aryl or heteroaryl, each of which is        optionally substituted with one or more C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with halogen, hydroxy or amino; or C₁₋₆-alkoxy,C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₃₋₆-cycloalkylsulfinyl,C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with halogen, hydroxy or amino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio,C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₁₋₆-alkoxy, C₁₋₆-alkylthio, perhalomethylthio,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl,di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino or C₁₋₆-dialkylamino, each ofwhich is optionally substituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₁₋₆-alkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl, each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio,C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl orC₃₋₆-cycloalkylamino each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio,C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl or arylsulfonyl, eachof which is optionally substituted with one or more C₁₋₆-alkyl orhalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with perhalomethyl, cyano or carboxy; or C₁₋₆-alkyl,C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, perhalomethylthio,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl,di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino or C₁₋₆-dialkylamino each ofwhich is optionally substituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with perhalomethyl, cyano or carboxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino orC₁₋₆-dialkylamino each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₁₋₆-alkyl or C₂₋₆-alkenyl, each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₃₋₆-cycloalkyl, C₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio,C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkylC₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aryl, heteroaryl or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl or heteroaryl each of which issubstituted with C₃₋₆-cycloalkyl, aryl or heteroaryl each of which isoptionally substituted with one or more C₁₋₆-alkyl or halogens; Inanother embodiment, the present invention is concerned with compounds offormula (I) wherein X₃ is aryl or heteroaryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl optionally substituted with one ormore substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, C₃₋₆-Cycloalkyl-C₁₋₆-alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl or heteroaryl, each of which is optionally substituted with        one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl optionally substituted with one ormore substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, aryl or heteroaryl, each of which is        optionally substituted with one or more C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with halogen, hydroxy oramino; or C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio,C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₃₋₆-cyCloalkylsulfinyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with halogen, hydroxy oramino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₁₋₆-alkoxy,C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₃₋₆-cycloalkylsulfinyl,C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₁₋₆-alkoxy,C₁₋₆-alkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl,C₁₋₆-alkylamino or C₁₋₆-dialkylamino, each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₁₋₆-alkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylsulfamoyl, each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₃₋₆-cycloalkoxy,C₃₋₆-cycloalkylthio, C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl orC₃₋₆-cycloalkylamino each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₃₋₆-cycloalkoxy,C₃₋₆-cycloalkylthio, C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl orarylsulfonyl, each of which is optionally substituted with one or moreC₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with perhalomethyl, cyanoor carboxy; or C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino orC₁₋₆-dialkylamino each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with perhalomethyl, cyanoor carboxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₁₋₆-alkyl,C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, perhalomethylthio,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl,di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino or C₁₋₆-dialkylamino each ofwhich is optionally substituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₁₋₆-alkyl orC₂₋₆-alkenyl, each of which is optionally substituted with one or moreC₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₃₋₆-cycloalkyl,C₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio, C₃₋₆-cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, aryl, heteroaryl orC₃₋₆-cycloalkylamino each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is aryl substituted with C₃₋₆-cycloalkyl, arylor heteroaryl each of which is optionally substituted with one or moreC₁₋₆-alkyl or halogens; In another embodiment, the present invention isconcerned with compounds of formula (I) wherein X₃ is aryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl optionally substituted with one ormore substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, C₃₋₆-Cycloalkyl-C₁₋₆-alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl or heteroaryl, each of which is optionally substituted with        one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl optionally substituted with one ormore of perhalomethyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted trifluoromethyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with C₁₋₆-alkyl, whichis optionally substituted with one or more C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with C₃₋₆-cycloalkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with C₁₋₆-alkylthio.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted withC₃₋₆-cycloalkylthio.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with perhalomethylthio.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with C₁₋₆-alkylsulfinyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted withC₃₋₆-cycloalkylsulfinyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl substituted with methyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl optionally substituted with one ormore of thienyl, which is optionally substituted with one or moreC₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is phenyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, C₃₋₆-Cycloalkyl-C₁₋₆-alkylsulfonyl,        arylsulfonyl, heteroarylsulfonyl, C₁₋₆-alkylsulfamoyl,        di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl or heteroaryl, each of which is optionally substituted with        one or more of C₁₋₆-alkyl or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen, perhalomethyl, or    -   C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio,        C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,        C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl,        C₃₋₆-cycloalkylsulfonyl, C₁₋₆-alkylamino, C₁₋₆-dialkylamino,        aryl or heteroaryl, each of which is optionally substituted with        one or more of C₁₋₆-alkyl or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen, or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, C₁₋₆-alkylamino,        C₁₋₆-dialkylamino, aryl or heteroaryl, each of which is        optionally substituted with one or more of C₁₋₆-alkyl or        halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl optionally substituted with oneor more substituents selected from

-   -   halogen, or    -   C₁₋₆-alkyl or aryl, each of which is optionally substituted with        one or more of C₁₋₆-alkyl or halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with halogen,hydroxy or amino; or C₁₋₆-alkoxy, C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio,C₃₋₆-cycloalkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₃₋₆-cycloalkylsulfinyl, C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with halogen,hydroxy or amino.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with C₁₋₆-alkoxy,C₃₋₆-cycloalkoxy, C₁₋₆-alkylthio, C₃₋₆-cycloalkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₃₋₆-cycloalkylsulfinyl,C₁₋₆-alkylsulfonyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino,C₁₋₆-dialkylamino, or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with C₁₋₆-alkoxy,C₁₋₆-alkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl,C₁_-alkylamino or C₁₋₆-dialkylamino, each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with C₁₋₆-alkylthio,perhalomethylthio, C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl,C₁₋₆-alkylsulfamoyl, each of which is optionally substituted with one ormore C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted withC₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio, C₃₋₆-Cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl, C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl or C₃₋₆-cycloalkylamino each of whichis optionally substituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted withC₃₋₆-cycloalkoxy, C₃₋₆-cycloalkylthio, C₃₋₆-Cycloalkylsulfinyl,C₃₋₆-cycloalkylsulfonyl or arylsulfonyl, each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with perhalomethyl,cyano or carboxy; or C₁₋₆-alkyl, C₂₋₆-alkenyl, C₁₋₆-alkoxy,C₁₋₆-alkylthio, perhalomethylthio, C₁₋₆-alkylsulfinyl,C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl, di-(C₁₋₆-alkyl)sulfamoyl,C₁₋₆-alkylamino or C₁₋₆-dialkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with perhalomethyl,cyano or carboxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with C₁₋₆-alkyl,C₂₋₆-alkenyl, C₁₋₆-alkoxy, C₁₋₆-alkylthio, perhalomethylthio,C₁₋₆-alkylsulfinyl, C₁₋₆-alkylsulfonyl, C₁₋₆-alkylsulfamoyl,di-(C₁₋₆-alkyl)sulfamoyl, C₁₋₆-alkylamino or C₁₋₆-dialkylamino each ofwhich is optionally substituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted with C₁₋₆-alkyl orC₂₋₆-alkenyl, each of which is optionally substituted with one or moreC₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted withC₃₋₆-cycloalkyl, C₃₋₆-cycloalkoxy, C₃₋₆-cyCloalkylthio,C₃₋₆-cycloalkylsulfinyl, C₃₋₆-cycloalkylsulfonyl,C₃₋₆-cycloalkyl-C₁₋₆-alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,aryl, heteroaryl or C₃₋₆-cycloalkylamino each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is heteroaryl substituted withC₃₋₆-cycloalkyl, aryl or heteroaryl each of which is optionallysubstituted with one or more C₁₋₆-alkyl or halogens; In anotherembodiment, the present invention is concerned with compounds of formula(I) wherein X₃ is heteroaryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is benzofuran optionally substituted with oneor more of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is benzothiophen optionally substituted withone or more of C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is pyridine optionally substituted with one ormore of aryl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein X₃ is thienyl optionally substituted with one ormore substituents selected from halogen or C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is arylene which is optionally substitutedwith one or more substituents selected from

-   -   halogen; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, aryloxy or aralkoxy each of which is        optionally substituted with one or more halogens; or    -   two of the substituents when placed in adjacent positions        together with the atoms to which they are attached form a five        membered carbon cycle.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more substituents selected from

-   -   halogen; or    -   C₁₋₆-alkyl, C₁₋₆-alkoxy, aryloxy or aralkoxy each of which is        optionally substituted with one or more halogens; or    -   two of the substituents when placed in adjacent positions        together with the atoms to which they are attached form a five        membered carbon cycle.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene where two of the substituentsplaced in adjacent positions together with the atoms to which they areattached form a five membered carbon cycle.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is benzofuranyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more substituents selected from halogen or C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith halogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more of C₁₋₆-alkyl optionally substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more of C₁₋₆-alkoxy optionally substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more of aryloxy optionally substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith one or more of aralkoxy optionally substituted with one or morehalogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene which is optionally substitutedwith methyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Ar is phenylene.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Y₁ is S.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Y₁ is O.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Y₂ is O.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Y₂ is S.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein Y₂ is CH₂.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein n is 1.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein n is 2.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₁ is hydrogen or a substituent selected fromC₁₋₆-alkyl, aralkyl, C₁₋₆-alkoxy, aryloxy, aralkoxy each of which isoptionally substituted with one or more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₁ is hydrogen or a substituent selected fromC₁₋₆-alkyl, C₁₋₆-alkoxy each of which is optionally substituted with oneor more halogens.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₁ is hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₁ is methyl or ethyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₁ is methoxy or ethoxy.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₂ is hydrogen or C₁₋₆-alkyl.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₂ is hydrogen.

In another embodiment, the present invention is concerned with compoundsof formula (I) wherein R₂ is methyl or ethyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein alkyl is methyl or ethyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein alkenyl is vinyl or 1-propenyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein alkynyl is 1-propynyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein alkenynyl is 1-pentene-4-yne.

In another embodiment, the present invention is concerned with compoundsof formula I wherein alkoxy is methoxy, ethoxy, isopropoxy orcyclopropoxy.

In another embodiment, the present invention is concerned with compoundsof formula I wherein aryl is phenyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein arylene is phenylene.

In another embodiment, the present invention is concerned with compoundsof formula I wherein halogen is bromine, fluorine or chlorine.

In another embodiment, the present invention is concerned with compoundsof formula I wherein perhalomethyl is trifluoromethyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein perhalomethoxy is trifluoromethoxy,

In another embodiment, the present invention is concerned with compoundsof formula I wherein heteroaryl is furyl or thienyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein heteroaryl is pyrazolyl, pyrrolyl or pyridyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein heteroaryl is benzofuryl or benzothienyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein heterocyclyl is pyrrolidinyl, piperidinyl,piperazinyl or morpholinyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein heteroarylene is thienylene.

In another embodiment, the present invention is concerned with compoundsof formula I wherein aralkyl is benzyl.

In another embodiment, the present invention is concerned with compoundsof formula I wherein aryloxy is phenoxy.

In another embodiment, the present invention is concerned with compoundsof formula I wherein aralkoxy is benzyloxy.

In another embodiment, the present invention is concerned with compoundsof formula I which are PPARδ agonists.

In another embodiment, the present invention is concerned with compoundsof formula I which are selective PPARδ agonists.

Examples of compounds of the invention are:

-   (E)-[2-Methyl-4-[3-phenyl-3-[4-(phenylethynyl)phenyl]allylsulfanyl]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]acetic    acid;-   (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)-allyloxy]-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-Chlorophenyl)-3-[4-(4-methylphenylethynyl)phenyl]allyloxy]-2-methylphenoxy]-acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-(3,3-dimethylbutynyl)phenyl]allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(dimethylamino)    propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(methylsulfanyl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetic    acid-   (E)-[4-[3-[4-[3-(Dimethylamino)propynyl)phenyl]-3-(4-fluorophenyl)allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(morpholin-4-yl)propynyl]-phenyl]allyloxy]phenoxy]acetic    acid;-   (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]phenoxy]acetic    acid;-   (Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]-acetic    acid;-   E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(pyrrolidin-1-yl)propynyl)phenyl]-allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(morpholin-4-yl)propynyl)phenyl]-allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(dimethylamino)propynyl)phenyl]-allyloxy]phenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-[N-(2-Hydroxyethyl)-N-methylamino]propynyl]phenyl]-3-(2-methylbenzo[b]-furan-5-yl)allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-(2-methyl-1,1-dioxobenzo[b]thiophen-5-ylethynyl)phenyl]-allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(6-phenylpyridin-3-yl)allyloxy]-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(N-cyclopropylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-(N,N-Dimethylamino)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-Cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-Cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(4-methylsulfinylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(4-methylpiperazin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-(3-[N-(2-hydroxyethyl)-N-methylamino]propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-[N-(2-hydroxyethyl)-N-methylamino]propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-(4-Cyclopropylsulfinylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]allyloxy]phenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetic    acid;-   (E)-[4-[3-[4-(Methylsulfinyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(methylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetic    acid;-   (Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Bromophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Bromophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic    acid;-   {4-[(Z)-3-(4-Fluoro-phenyl)-3-(4-phenylethynyl-phenyl)-allyloxy]-2-methyl-phenoxy}-acetic    acid;-   (4-{(E)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)acetic    acid;-   (4-{(Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)acetic    acid;-   (2-Methyl-4-{(Z)-3-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-phenoxy)acetic    acid;-   {2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-acetic    acid;-   {2-Methyl-4-[(E)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-acetic    acid; or    a salt thereof with a pharmaceutically acceptable acid or base, or    any optical isomer or mixture of optical isomers, including a    racemic mixture, or any tautomeric forms.

Other examples of compounds of the invention are:

-   (E)-[4-[3-(4-Bromophenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-1-[4-[4-[1-(4-Bromophenyl)-3-[4-(carboxymethoxy)-3-methylphenoxy]propenyl]-phenylethynyl]benzyl]piperidine-4-carboxylic    acid;-   (Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetic    acid;-   (Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   Methyl    (E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate;-   (Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionic    acid;-   (Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetic    acid;-   (Z)-[4-[3-(Benzo[b]thiophen-2-yl)-3-[4-[4-(trifluoromethylphenyl)ethynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic    acid;-   (E)-[7-[3-[4-[3-(Morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetic    acid; or    a salt thereof with a pharmaceutically acceptable acid or base, or    any optical isomer or mix ture of optical isomers, including a    racemic mixture, or any tautomeric forms.

The present invention also encompasses pharmaceutically acceptable saltsof the present compounds. Such salts include pharmaceutically acceptableacid addition salts, pharmaceutically acceptable base addition salts,pharmaceutically acceptable metal salts, ammonium and alkylated ammoniumsalts. Acid addition salts include salts of inorganic acids as well asorganic acids. Representative examples of suitable inorganic acidsinclude hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric,nitric acids and the like. Representative examples of suitable organicacids include formic, acetic, trichloroacetic, trifluoroacetic,propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic,malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic,methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic,bismethylene salicylic, ethanedisulfonic, gluconic, citraconic,aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic,benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates,phosphates, perchlorates, borates, acetates, benzoates,hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.Further examples of pharmaceutically acceptable inorganic or organicacid addition salts include the pharmaceutically acceptable salts listedin J. Pharm. Sci. 1977, 66, 2, which is incorporated herein byreference. Examples of metal salts include lithium, sodium, potassium,magnesium, zinc, calcium salts and the like. Examples of amines andorganic amines include ammonium, methylamine, dimethylamine,trimethylamine, ethylamine, diethylamine, propylamine, butylamine,tetramethylamine, ethanolamine, diethanolamine, triethanolamine,meglumine, ethylenediamine, choline, N,N′-dibenzylethylenediamine,N-benzylphenylethylamine, N-methyl-D-glucamine, guanidine and the like.Examples of cationic amino acids include lysine, arginine, histidine andthe like.

The pharmaceutically acceptable salts are prepared by reacting thecompound of formula I with 1 to 4 equivalents of a base such as sodiumhydroxide, sodium methoxide, sodium hydride, potassium t-butoxide,calcium hydroxide, magnesium hydroxide and the like, in solvents likeether, THF, methanol, t-butanol, dioxane, isopropanol, ethanol etc.Mixture of solvents may be used. Organic bases like lysine, arginine,diethanolamine, choline, guandine and their derivatives etc. may also beused. Alternatively, acid addition salts wherever applicable areprepared by treatment with acids such as hydrochloric acid, hydrobromicacid, nitric acid, sulfuric acid, phosphoric acid, p-toluenesulphonicacid, methanesulfonic acid, acetic acid, citric acid, maleic acidsalicylic acid, hydroxynaphthoic acid, ascorbic acid, palmitic acid,succinic acid, benzoic acid, benzenesulfonic acid, tartaric acid and thelike in solvents like ethyl acetate, ether, alcohols, acetone, THF,dioxane etc. Mixture of solvents may also be used.

The stereoisomers of the compounds forming part of this invention may beprepared by using reactants in their single enantiomeric form in theprocess wherever possible or by conducting the reaction in the presenceof reagents or catalysts in their single enantiomer form or by resolvingthe mixture of stereoisomers by conventional methods. Some of thepreferred methods include use of microbial resolution, enzymaticresolution, resolving the diastereomeric salts formed with chiral acidssuch as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid,and the like wherever applicable or chiral bases such as brucine, (R)-or (S)-phenylethylamine, cinchona alkaloids and their derivatives andthe like. Commonly used methods are compiled by Jaques et al in“Enantiomers, Racemates and Resolution” (Wiley Interscience, 1981). Morespecifically the compound of formula I may be converted to a 1:1 mixtureof diastereomeric amides by treating with chiral amines, aminoacids,aminoalcohols derived from aminoacids; conventional reaction conditionsmay be employed to convert acid into an amide; the dia-stereomers may beseparated either by fractional crystallization or chromatography and thestereoisomers of compound of formula I may be prepared by hydrolysingthe pure diastereomeric amide.

Various polymorphs of compound of general formula I forming part of thisinvention may be prepared by crystallization of compound of formula Iunder different conditions. For example, using different solventscommonly used or their mixtures for recrystallization; crystallizationsat different temperatures; various modes of cooling, ranging from veryfast to very slow cooling during crystallizations. Polymorphs may alsobe obtained by heating or melting the compound followed by gradual orfast cooling. The presence of polymorphs may be determined by solidprobe nmr spectroscopy, ir spectroscopy, differential scanningcalorimetry, powder X-ray diffraction or such other techniques.

The compounds of the present invention may form solvates with standardlow molecular weight solvents using methods well known to the personskilled in the art. Such solvates are also contemplated as being withinthe scope of the present invention. Examples of solvates are thehydrates, which the present compounds are able to form.

The invention also encompasses prodrugs of the present compounds, whichon administration undergo chemical conversion by metabolic processesbefore becoming active pharmacological substances. In general, suchprodrugs will be functional derivatives of the present compounds, whichare readily convertible in vivo into the required compound of theformula (I). Conventional procedures for the selection and preparationof suitable prodrug derivatives are described, for example, in “Designof Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The invention also encompasses active metabolites of the presentcompounds.

The invention also relates to pharmaceutical compositions comprising, asan active ingredient, at least one compound of the formula I or anyoptical or geometric isomer or tautomeric form thereof includingmixtures of these or a pharmaceutically acceptable salt thereof togetherwith one or more pharmaceutically acceptable carriers or diluents.

The invention also provides novel compounds of the formula I for use intherapy.

In an aspect, the present invention provides novel compounds orpharmaceutically acceptable salts thereof that are useful as PPAR-6activators.

In another aspect, the present invention provides novel compounds thatimprove mitochondrial energy output.

In another aspect, the present invention provides novel pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to a method of treatingand/or preventing Type I or Type II diabetes.

In a still further aspect, the present invention relates to the use ofone or more compounds of the general formula I or pharmaceuticallyacceptable salts thereof for the preparation of a pharmaceuticalcomposition for the treatment and/or prevention of Type I or Type IIdiabetes.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of IGT.

In a still further aspect, the present compounds are useful for thetreatment and/or prevention of Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from IGT to Type 2 diabetes.

In a still further aspect, the present compounds are useful for thedelaying or prevention of the progression from non-insulin requiringType 2 diabetes to insulin requiring Type 2 diabetes.

In a still further aspect, the present compounds are useful aspharmaceutical compositions having cholesterol and/or glucose loweringeffects.

In a still further aspect, the present compounds reduce blood glucoseand triglyceride levels.

In a still further aspect, the present compounds are useful inincreasing insulin sensitivity.

In another aspect, the present compounds are cholesterol and/or glucoselowering and are accordingly useful in the treatment of diseases such astype 2 diabetes, dyslipidemia, syndrome X (including the metabolicsyndrome, i.e. impaired glucose tolerance, insulin resistance,hypertrigyceridaemia and/or obesity), cardiovascular diseases (includingatherosclerosis) and hypercholesteremia.

In another aspect, the present compounds reduce blood glucose andtriglyceride levels and are accordingly useful for the treatment and/orprevention of ailments and disorders such as diabetes and/or obesity.

In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of insulin resistance (Type 2 diabetes),impaired glucose tolerance, dyslipidemia, disorders related to SyndromeX such as hypertension, obesity, insulin resistance, hyperglycaemia,atherosclerosis, artherosclerosis, hyperlipidemia, coronary arterydisease, myocardial ischemia and other cardiovascular disorders.

In still another aspect, the present compounds are useful for thetreatment and/or prophylaxis of diseases or complications related toatherosclerosis such as coronary artery diseases, coronary heartdiseases, heart attack, myocardial infarct, coronary infarct, transientischemic attack (TIA) or stroke.

In still another aspect, the present compounds are effective indecreasing apoptosis in mammalian cells such as beta cells of Islets ofLangerhans.

In still another aspect, the present compounds are useful for thetreatment of certain renal diseases including glomerulonephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis.

In still another aspect, the present compounds may also be useful forimproving cognitive functions in dementia, treating diabeticcomplications, psoriasis, polycystic ovarian syndrome (PCOS) andprevention and treatment of bone loss, e.g. osteoporosis.

In yet another aspect, the invention also relates to the use of thepresent compounds, which after administration lower the bio-markers ofatherosclerosis like, but not limited to, c-reactive protein (CRP), TNFαand IL-6.

The present compounds may also be administered in combination with oneor more further pharmacologically active substances eg., selected fromantiobesity agents, antidiabetics, antihypertensive agents, agents forthe treatment and/or prevention of complications resulting from orassociated with diabetes and agents for the treatment and/or preventionof complications and disorders resulting from or associated withobesity.

Thus, in a further aspect of the invention the present compounds may beadministered in combination with one or more antiobesity agents orappetite regulating agents.

Such agents may be selected from the group consisting of CART (cocaineamphetamine regulated transcript) agonists, NPY (neuropeptide Y)antagonists, MC4 (melanocortin 4) agonists, orexin antagonists, TNF(tumor necrosis factor) agonists, CRF (corticotropin releasing factor)agonists, CRF BP (corticotropin releasing factor binding protein)antagonists, urocortin agonists, 33 agonists, MSH(melanocyte-stimulating hormone) agonists, MCH (melanocyte-concentratinghormone) antagonists, CCK (cholecystokinin) agonists, serotoninre-uptake inhibitors, serotonin and noradrenaline re-uptake inhibitors,mixed serotonin and noradrenergic compounds, 5HT (serotonin) agonists,bombesin agonists, galanin antagonists, growth hormone, growth hormonereleasing compounds, TRH (thyreotropin releasing hormone) agonists, UCP2 or 3 (uncoupling protein 2 or 3) modulators, leptin agonists, DAagonists (bromocriptin, doprexin), lipase/amylase inhibitors, RXR(retinoid X receptor) modulators or TR P agonists.

In one embodiment of the invention the antiobesity agent is leptin.

In another embodiment the antiobesity agent is dexamphetamine oramphetamine.

In another embodiment the antiobesity agent is fenfluramine ordexfenfluramine.

In still another embodiment the antiobesity agent is sibutramine.

In a further embodiment the antiobesity agent is orlistat.

In another embodiment the antiobesity agent is mazindol or phentermine.

Suitable antidiabetics comprise insulin, GLP-1 (glucagon like peptide-1)derivatives such as those disclosed in WO 98/08871 to Novo Nordisk A/S,which is incorporated herein by reference as well as orally activehypoglycaemic agents.

The orally active hypoglycaemic agents preferably comprisesulphonylureas, biguanides, meglitinides, glucosidase inhibitors,glucagon antagonists such as those disclosed in WO 99/01423 to NovoNordisk A/S and Agouron Pharmaceuticals, Inc., GLP-1 agonists, potassiumchannel openers such as those disclosed in WO 97/26265 and WO 99/03861to Novo Nordisk A/S which are incorporated herein by reference, DPP-IV(dipeptidyl peptidaseIV) inhibitors, inhibitors of hepatic enzymesinvolved in stimulation of gluconeogenesis and/or glycogenolysis,glucose uptake modulators, compounds modifying the lipid metabolism suchas antihyperlipidemic agents and antilipidemic agents as HMG CoAinhibitors (statins), compounds lowering food intake, RXR agonists andagents acting on the ATP-dependent potassium channel of the β-cells.

In one embodiment of the invention the present compounds areadministered in combination with insulin.

In a further embodiment the present compounds are administered incombination with a sulphonylurea eg. tolbutamide, glibenclamide,glipizide or glicazide.

In another embodiment the present compounds are administered incombination with a biguanide eg. metformin.

In yet another embodiment the present compounds are administered incombination with a meglitinide eg. repaglinide or senaglinide.

In a further embodiment the present compounds are administered incombination with an α-glucosidase inhibitor eg. miglitol or acarbose.

In another embodiment the present compounds are administered incombination with an agent acting on the ATP-dependent potassium channelof the β-cells eg. tolbutamide, glibenclamide, glipizide, glicazide orrepaglinide.

Furthermore, the present compounds may be administered in combinationwith nateglinide.

In still another embodiment the present compounds are administered incombination with an antihyperlipidemic agent or antilipidemic agent eg.cholestyramine, colestipol, clofibrate, gemfibrozil, fenofibrate,bezafibrate, tesaglitazar, EML-4156, LY-518674, LY-519818, MK-767,atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin,cerivastin, acipimox, ezetimibe probucol, dextrothyroxine or nicotinicacid.

In yet another embodiment the present compounds are administered incombination with a thiazolidinedione e.g. troglitazone, ciglitazone,pioglitazone or rosiglitazone.

In a further embodiment the present compounds are administered incombination with more than one of the above-mentioned compounds eg. incombination with a sulphonylurea and metformin, a sulphonylurea andacarbose, repaglinide and metformin, insulin and a sulphonylurea,insulin and metformin, insulin, insulin and lovastatin, etc.

Furthermore, the present compounds may be administered in combinationwith one or more antihypertensive agents. Examples of antihypertensiveagents are β-blockers such as alprenolol, atenolol, timolol, pindolol,propranolol and metoprolol, ACE (angiotensin converting enzyme)inhibitors such as benazepril, captopril, enalapril, fosinopril,lisinopril, quinapril and ramipril, calcium channel blockers such asnifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazemand verapamil, and α-blockers such as doxazosin, urapidil, prazosin andterazosin. Further reference can be made to Remington: The Science andPractice of Pharmacy, 19^(th) Edition, Gennaro, Ed., Mack PublishingCo., Easton, Pa., 1995.

It should be understood that any suitable combination of the compoundsaccording to the invention with one or more of the above-mentionedcompounds and optionally one or more further pharmacologically activesubstances are considered to be within the scope of the presentinvention.

The present invention also relates to a process for the preparation ofthe above said novel compounds, their derivatives, their analogs, theirtautomeric forms, their stereoisomers, their polymorphs, theirpharmaceutically acceptable salts or pharmaceutically acceptablesolvates.

Pharmaceutical Compositions

The compounds of the invention may be administered alone or incombination with pharmaceutically acceptable carriers or excipients, ineither single or multiple doses. The pharmaceutical compositionsaccording to the invention may be formulated with pharmaceuticallyacceptable carriers or diluents as well as any other known adjuvants andexcipients in accordance with conventional techniques such as thosedisclosed in Remington: The Science and Practice of Pharmacy, 19^(th)Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995. Thecompositions may appear in conventional forms, for example capsules,tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of formula I or apharmaceutically acceptable acid addition salt thereof, associated witha pharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent may include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax. The formulations may also include wetting agents,emulsifying and suspending agents, preserving agents, sweetening agentsor flavouring agents. The formulations of the invention may beformulated so as to provide quick, sustained, or delayed release of theactive ingredient after administration to the patient by employingprocedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, transdermal or parenteral e.g.rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular,intranasal, ophthalmic solution or an ointment, the oral route beingpreferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound offormula I dissolved or suspended in a liquid carrier, in particular anaqueous carrier, for aerosol application.

The carrier may contain additives such as solubilizing agents, e.g.propylene glycol, surfactants, absorption enhancers such as lecithin(phosphatidylcholine) or cyclodextrin, or preservatives such asparabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet which may be prepared by conventional tablettingtechniques may contain:

Core:

  Active compound (as free compound or salt thereof)   5 mg Colloidalsilicon dioxide (Aerosil) 1.5 mg Cellulose, microcryst. (Avicel)  70 mgModified cellulose gum (Ac-Di-Sol) 7.5 mg Magnesium stearate Ad.

Coating:

  HPMC approx.   9 mg *Mywacett 9-40 T approx. 0.9 mg *Acylatedmonoglyceride used as plasticizer for film coating.

If desired, the pharmaceutical composition of the invention may comprisethe compound of formula (I) in combination with furtherpharmacologically active substances such as those described in theforegoing.

The compounds of the invention may be administered to a mammal,especially a human in need of such treatment, prevention, elimination,alleviation or amelioration of diseases related to the regulation ofblood sugar.

Such mammals include also animals, both domestic animals, e.g. householdpets, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range. Atypical oral dosage is in the range of from about 0.001 to about 100mg/kg body weight per day, preferably from about 0.01 to about 50 mg/kgbody weight per day, and more preferred from about 0.05 to about 10mg/kg body weight per day administered in one or more dosages such as 1to 3 dosages. The exact dosage will depend upon the frequency and modeof administration, the sex, age, weight and general condition of thesubject treated, the nature and severity of the condition treated andany concomitant diseases to be treated and other factors evident tothose skilled in the art.

The formulations may conveniently be presented in unit dosage form bymethods known to those skilled in the art. A typical unit dosage formfor oral administration one or more times per day such as 1 to 3 timesper day may contain of from 0.05 to about 1000 mg, preferably from about0.1 to about 500 mg, and more preferred from about 0.5 mg to about 200mg.

Any novel feature or combination of features described herein isconsidered essential to this invention.

EXAMPLES

The following examples and general procedures refer to intermediatecompounds and final products identified in the specification and in thesynthesis schemes. The preparation of the compounds of the presentinvention is described in detail using the following examples.Occasionally, the reaction may not be applicable as described to eachcompound included within the disclosed scope of the invention. Thecompounds for which this occurs will be readily recognised by thoseskilled in the art. In these cases the reactions can be successfullyperformed by conventional modifications known to those skilled in theart, that is, by appropriate protection of interfering groups, bychanging to other conventional reagents, or by routine modification ofreaction conditions. Alternatively, other reactions disclosed herein orotherwise conventional will be applicable to the preparation of thecorresponding compounds of the invention. In all preparative methods,all starting materials are known or may easily be prepared from knownstarting materials. The structures of the compounds are confirmednuclear magnetic resonance (NMR). NMR shifts (6) are given in parts permillion (ppm. Mp is melting point and is given in OC.

The abbreviations as used in the examples have the following meaning:

THF: tetrahydrofuran

DMSO: dimethylsulfoxide

CDCl₃: deutorated chloroform

DMF: N,N-dimethylformamide

min: minutes

h: hours

General procedure (A)

Step A:

Reacting a compound of formula II

wherein, X₃ is defined as above, with propargyl alcohol usingSonogashira reaction conditions to give a compound of formula III

wherein X₃ is defined as above.Step B:

Coupling compound III with halogen-X₂-halogen using LiAlH4 followed bydirect Pdcoupling to give in a one-pot procedure a compound of formulaIV

wherein X₂ and X₃ are defined as above, andStep C:

Reacting the compound of formula IV, wherein X₂ and X₃ are defined asabove, with a compound of formula V

wherein Y₁, Ar, Y₂, Z and R₂ are defined as above, except that R₂ is nothydrogen, under Mitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like, to obtain acompound of formula VI

wherein X₂, X₃, Y₁, Y₂, Ar, Z and R₂ are defined as above, except thatR₂ is not hydrogen.Step D:

Reacting a compound of formula VI, wherein X₂, X₃, Y₁, Y₂, Ar, Z and R₂are defined as above, with a compound of formula VII,

wherein X₁ is as defined as above, using Sonogashira reaction conditionsto give a compound of formula I, wherein X₁, X₂, X₃, Y₁, Y₂, Ar, Z andR₂ are defined as above, except that R₂ is not hydrogen.General Procedure (B)Step A:

Converting the —OH functionality in the compound of formula IV, whereinX₂ and X₃ are defined as above, to an appropriate leaving group (L) suchas p-toluenesulfonate, methanesulfonate, halogen (for example by methodsaccording to: Houben-Weyl, Methoden der organischen Chemie, AlkoholeIII, 6/1b, Thieme-Verlag 1984, 4th Ed., pp. 927-939; ComprehensiveOrganic Transformations. A guide to functional group preparations, VCHPublishers 1989, 1^(st) Ed., pp. 353-363 and J. Org. Chem., Vol. 36(20), 3044-3045, 1971), triflate and the like, to give a compound offormula VIII

wherein, X₂ and X₃ are defined as above and L is a leaving group such asp-toluenesulfonate, methanesulfonate, halogen, triflate and the like.Step B:

Reacting the compound of formula VIII,

wherein L is a leaving group such as p-toluenesulfonate,methanesulfonate, halogen, triflate and the like and wherein X₂ and X₃are defined as above with a compound of formula V

wherein Y₁, Ar, Y₂, Z and R₂ are defined as above, except that R₂ is nothydrogen, to give a compound of formula VI

wherein X₂, X₃, Y₁, Y₂, Ar, Z and R₂ are defined as above, except thatR₂ is not hydrogen.General Procedure (C)Step A:

Reacting an compound of formula IX

wherein X₂, X₃ and R₁ are defined as above, with a compound of formulaVII

wherein X₁ is as defined as above, under Sonogashira reactionconditions, to give a compound of formula X,

wherein X₁, X₂, X₃, Y₁, Y₂, Ar, Z, R₁ and R₂ are defined as above,except that R₂ is not hydrogen.Step B:

Reacting a compound of formula X,

wherein X₂, X₃, Y₁, Y₂, Ar, Z, R1 and R₂ are defined as above, with acompound of formula VII,

wherein X₁ is as defined as above, using Sonogashira reaction conditionsto give a compound of formula I, wherein X₁, X₂, X₃, Y₁, Y₂, Ar, Z andR₂ are defined as above, except that R₂ is not hydrogen.General Procedure (D)Step A:

By chemical or enzymatic saponification of a compound of formula Iwherein X₁, X₂, X₃, Y₁, Y₂, Ar, Z, R₁ and R₂ are defined as above,except that R₂ is not hydrogen, to give a compound of formula I whereinX₁, X₂, X₃, Y¹, Y₂, Ar, Z, R₁ and R₂ are defined as above, except thatR₂ is hydrogen.

General Procedure (E)

Step A:

Reacting a compound of formula XI

wherein X₁, X₂ and X₃ are defined as above, through a Horner-Emmons-likeprocess with for example (EtO)₂PO(CHR₁)COOR₆ (wherein R₆ is an alkylgroup), in the presence of a base such as sodium hydride, EtONa and thelike to give a compound of formula XII

wherein X₁, X₂, X₃, R₁ and R₆ are defined as aboveStep B:

Reducing the compound of formula XII, wherein X₁, X₂, X₃, R₁ and R₆ aredefined as above with a suitable reagent such as diisobutylaluminiumhydride, to give a compound of formula XIII

wherein X₁, X₂, X₃ and R₁ are defined as above, andStep C:

Reacting the compound of formula XIII, wherein X₁, X₂, X₃ and R₁ aredefined as above, with a compound of formula V, wherein Y₁, Ar, Y₂, Zand R₂ are defined as above, except that R₂ is not hydrogen, underMitsunobu conditions, using a reagent such astriphenylphosphine/diethylazodicarboxylate and the like, to obtain acompound of formula I, wherein X₁, X₂, X₃, X₄, Y₁, Y₂, Ar, Z, R₁ and R₂are defined as above, except that R₂ is not hydrogen.

Example 1(E)-[2-Methyl-4-[3-phenyl-3-[4-(phenylethynyl)phenyl]allylsulfanyl]phenoxy]aceticAcid

In argon atmosphere, 0.15 M Solution of tri-tert-butylphosphine incyclohexane (12.0 mL, 18.0 mmol) was added to a stirred suspension ofcopper(I) iodide (350 mg, 1.8 mmol) anddichloro(bisbenzonitrile)palladium (350 mg, 0.9 mmol) in tetrahydrofuran(100 mL) at ambient temperature. The mixture was stirred for 5 min,N,N-diisopropylamine (4.5 mL, 30 mmol) was added, the mixture wasstirred for next 5 min and then a solution of 4-bromobenzophenone (3.92g, 15 mmol) and phenylacetylene (2.30 g, 22.5 mmol) in tetrahydrofuran(20 mL) was added dropwise during 15 min. The reaction mixture wasstirred at ambient temperature overnight and then diluted with benzene(200 mL). The benzene solution was washed with water (2×80 mL) and 1.5 Maqueous solution of tartaric acid (30 mL); the organic solution wasdried with anhydrous magnesium sulfate and subsequently evaporated invacuo. The residue was purified by column chromatography (silica gelFluka 60, hexane/ethyl acetate 95:5) yieldingphenyl-[4-(phenylethynyl)phenyl]methanone.

Yield: 4.11 g (97%).

R_(F) (SiO₂, benzene) 0.55.

¹H NMR spectrum (200 MHz, CDC₃, δ_(H)): 7.82-7.76 (m, 4H); 7.67-7.44 (m,7H); 7.42-7.30 (m, 3H).

A solution of triethyl phosphonoacetate (6.53 g, 29.1 mmol) in drytetrahydrofuran (20 mL) was added dropwise to a suspension of sodiumhydride (80% suspension in oil, 873 mg, 29.1 mmol; washed three timeswith hexane) in dry tetrahydrofuran (50 mL) under nitrogen atmosphere(20 min). When the gas evolution deceased, the suspension was heated toreflux for 10 min. The mixture was allowed to cool down, a solution ofthe above ketone in dry tetrahydrofuran (40 mL) was added dropwise andthe resulting reaction mixture was refluxed for 90 min. The mixture wasallowed to cool down and poured into 5% aqueous solution of citric acid(200 mL). Ether was added (100 mL), organic layer was separated and theaqueous layer was extracted with ether (50 mL). The combined organicsolutions were washed with 10% aqueous solution of sodium hydrogencarbonate (50 mL), water (2×50 mL) and dried with anhydrous magnesiumsulfate. The residue obtained by evaporation of the organic solution waspurified by column chromatography (silica gel Fluka 60, hexane/ethylacetate 95:5) yielding a mixture of both isomers (5.05 g). The productwas recrystallized from the mixture of n-heptane/benzene/ethanol to givepure ethyl (E)-3-phenyl-3-[4-(phenylethynyl)phenyl]acrylate(configuration assigned according to NOE experiment).

Yield of (E)-isomer: 2.25 g (44%).

M.p. 86-88° C. (n-heptane/benzene/ethanol).

R_(F) (SiO₂, hexane/ethyl acetate 95:5) 0.40.

¹H NMR spectrum (200 MHz, DMSO-d₆, δ_(H)): 7.65-7.05 (m, 14H); 6.38 (s,1H); 4.08 (q, J=8.0 Hz, 2H); 1.16 (t, J=8.0 Hz, 3H).

Mother liquor from crystallization of the main crop was evaporatedgiving 2.45 g (48%) of mixture of both isomers.

In atmosphere of argon, 1 M solution of diisobutylaluminum hydride intetrahydrofuran (5 mL, 5 mmol) was added dropwise to a cooled (−20° C.)solution of the above (E)-ester (1.90 g; 5.39 mmol) in drytetrahydrofuran (30 mL). The reaction mixture was allowed to warm up to−15° C., stirred at the temperature for 30 min and then allowed to warmup to ambient temperature and stirred overnight. The mixture was cooledto −10° C. again, methanol (5 mL) and subsequently 15% aqueoushydrochloric acid (7 mL) were added and the mixture was allowed to warmup to ambient temperature. The mixture was diluted with ether (100 mL),the organic layer was washed with brine (30 mL), dried with anhydrousmagnesium sulfate and subsequently evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, hexane/ethylacetate 85:15) giving a crystalline product which was recrystallizedfrom a mixture ethanol/n-heptane (7:3, 10 mL) giving(E)-3-phenyl-3-[4-(phenylethynyl)phenyl]allyl alcohol.

Yield: 655 mg (39%).

M.p. 115-117° C.

R_(F) (SiO₂, hexane/ethyl acetate 85:15) 0.25.

¹H NMR spectrum (200 MHz, CDCl₃, δ_(H)): 7.62-7.18 (m, ˜14H); 6.27 (t,J=6.8 Hz, 1H); 4.27 (d, J=6.8 Hz, 2H); 1.54 (bs, 1H).

In atmosphere of nitrogen, tetrabromomethane (500 mg, 1.51 mmol) wasadded to an ice-water cooled solution of the above hydroxy derivative(470 mg, 1.51 mmol) and triphenylphosphine (420 mg, 1.60 mmol) in drymethylene chloride (20 mL). The mixture was stirred for 2 h undercooling and for further 2 h at ambient temperature, filtered throughshort path of silica gel and evaporated in vacuo. The residue wasdissolved in tetrahydrofuran (19 mL), N,N-diisopropylethylamine (233 mg,1.80 mmol) and subsequently a solution of ethyl(4-mercapto-2-methylphenoxy)acetate (404 mg, 1.90 mmol) intetrahydrofuran (1 mL) were added and the resulting solution was stirredfor 18 h. The mixture was evaporated in vacuo and the residue waspurified by column chromatography (silica gel Fluka 60, hexane/ethylacetate 95:5) yielding of ethyl(E)-[2-Methyl-4-[3-phenyl-3-[4-(phenylethynyl)phenyl]allylsulfanyl]phenoxy]acetateas an oil.

Yield: 365 mg (47%).

R_(F) (SiO₂, hexane/ethyl acetate 9:1) 0.45.

¹H NMR spectrum (200 MHz, DMSO-d₆, δ_(H)): 7.58-7.15 (m, ˜15H); 6.81 (d,2H); 6.56 (d, 1H); 6.13 (d, 1H); 4.62 (s, 1H); 4.23 (q, 2H); 3.52 (d,2H); 2.22 (s, 3H); 1.25 (t, 3H).

In atmosphere of nitrogen, a solution of lithium hydroxide monohydrate(629 mg, 1.66 mmol) in distilled water (10 mL) was added to an ice-watercooled solution of the above ester (350 mg, 1.11 mmol) in a mixture oftetrahydrofuran (50 mL) and methanol (10 mL). The resulting solution wasstirred for 2 h under cooling, 2 M aqueous solution of tartaric acid (2mL) was added and the resulting solution was diluted with water (30 mL).The mixture was extracted with ether (3×30 mL); the collected organicsolutions were washed with brine (30 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, chloroform/methanol 95:5) to yieldthe title acid.

Yield: 250 mg (46%).

R_(F) (SiO₂, chloroform/methanol, 9:1): 0.25.

¹H NMR spectrum (200 MHz, AcOH-d₄, δ_(H)): 7.60-7.10 (m, ˜14H); 6.88 (m,2H); 6.79 (d, 1H); 6.16 (bp, 1H); 4.73 (s, 2H); 3.52 (d, 2H); 2.18 (s,3H).

A solution of L-Lysine (64 mg, 0.438 mmol) in water (2 mL) was added toa solution of the above acid (226 mg, 0.461 mmol) in tetrahydrofuran (30mL). The mixture was stirred for 1 h, evaporated in vacuo and theresidue was three times triturated with anhydrous ether yieldingL-lysinate of the title acid.

Yield: 190 mg (68%).

¹H NMR spectrum (200 MHz, AcOH-d₄, δ_(H)): 7.65-7.05 (m, ˜6H); 6.88 (m,2H); 6.79 (d, 1H); 6.16 (bp, 1H); 4.72 (s, ˜2H); 4.05 (m, 1H); 3.53 (m,˜2H); 3.08 (m, 2H); 2.18 (s, ˜3H); 1.95-1.40 (m, overlap, ˜6H).

Example 2(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]aceticAcid

A solution of 1,4-dibromobenzene (23.6 g, 100.0 mmol) in drytetrahydrofuran (100 mL) was degassed and copper(I)iodide (570 mg, 3.0mmol), tetrakis(triphenylphosphine)palladium (3.4 g, 3.0 mmol) anddiazobicycloundecene (18.2 g, 120.0 mmol) were added. The reactionsolution was degassed again and propargyl alcohol (6.7 g, 120.0 mmol)was added dropwise under inert atmosphere at 0° C. The reaction wasstirred at 0° C. for 1 h and next 4 h at 50° C. The solution was thentreated with brine (20 mL) and acidified with 2 M hydrochloric acid (20mL). The organic phase was isolated and the aqueous phase was extractedwith ether (4×30 mL). The combined organic phases were dried withmagnesium sulfate and concentrated in vacuo yielding brown solid.Product was purified by crystallization from hexane yielding yellowishdust of 3-(4-bromophenyl)prop-2-yn-1-ol.

Yield: 10 g (49%).

M.p.: 65-68° C. (hexane).

R_(f) (hexane/ethyl acetate 90:10): 0.10.

Sodium methoxide (0.27 g, 0.5 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (12 mL, 12 mmol). The mixture wascooled to 0° C. and a solution of 3-(4-bromophenyl)prop-2-yn-1-ol (0.422g, 2.0 mmol) in tetrahydrofuran (50 mL) was slowly added. The reactionwas stirred for at 0° C. for 3 h, ethyl acetate (2.6 mL, 30 mmol) wasadded and the mixture was stirred for further 10 min without cooling.Iodobenzene (2.7 g, 13 mmol), anhydrous zinc bromide (1.4 g, 6 mmol),and tris(dibenzylideneacetone)dipalladium chloroform complex (0.50 g,0.5 mmol) were added and the mixture was evacuated and kept undernitrogen. A solution of tri-tert-butylphosphine in cyclohexane (6.7 mL,1 mmol) was added and the mixture was heated at 60° C. for 16 h.Methanol (10 mL) was added and the resulting mixture was stirred foradditional 1 h. The reaction mixture was poured into water, acidifiedwith hydrochloric acid and extracted with ethyl acetate (3×100 mL).Organic layers were combined, dried with anhydrous sodium sulphate,evaporated in vacuo and the residue was purified by columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-70:30)affording (E)-3-(4-bromophenyl)-3-phenylprop-2-en-1-ol.

Yield: 2.8 g (32%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1) 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42-7.34 (m, 5H); 7.15-7.05(m, 4H); 6.23 (t, J=6.9 Hz, 1H); 4.21 (d, J=4.8 Hz, 2H).

The above allyl alcohol (0.889 g, 3.0 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.770 g, 3.9 mmol; see below) andtriphenylphosphine (1.30 g, 5 mmol) were dissolved in a mixture ofanhydrous toluene (12 mL) and tetrahydrofuran (4 mL). The mixture wascooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate(0.85 g, 4.2 mmol) was added dropwise. The reaction mixture was stirredat 0° C. for 3 h and then at 25° C. for 16 h. The solvents wereevaporated in vacuo and the residue was submitted to columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 98:2-90:10)affording methyl(E)-[4-[3-(4-bromophenyl)-3-phenylallyloxy]-2-methylphenoxy]acetate.

Yield: 0.70 g (50%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1) 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.35 (m, 5H); 7.20-7.11(m, 4H); 6.70-6.55 (m, 3H); 6.23 (t, J=6.6 Hz, 1H); 4.58 (s, 2H); 4.51(d, J=6.6 Hz, 2H); 3.80 (s, 3H); 2.24 (s, 3H).

Dry triethylamine (8 mL), copper(I) iodide (29 mg, 0.152 mmol) andtetrakis(triphenylphosphine)palladium (68 mg, 0.059 mmol) were added toa degassed solution of the above ester (448 mg, 0.931 mmol) andN-propargylmorpholine (291 mg, 2.32 mmol) in dry tetrahydrofuran (18mL). In atmosphere of argon, the resulting mixture was heated at 50° C.for 10 h, cooled down and subsequently evaporated in vacuo. The residuewas dissolved in dichloromethane (20 mL); the solution was washed withwater (3×10 mL), dried with anhydrous magnesium sulfate and evaporatedin vacuo. The residue was purified by column chromatography (silica gelFluka 60, hexanes/ethyl acetate 4:1-1:1) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-phenylallyloxy]phenoxy]acetateas an oil.

Yield: 138 mg (29%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1) 0.10.

In atmosphere of argon, a solution of lithium hydroxide monohydrate(16.9 mg, 0.404 mmol) in distilled water (1 mL) was added to anice-water cooled solution of the above ester (138 mg, 0.270 mmol) intetrahydrofuran/methanol mixture (5:1; 6 mL). The resulting solution wasstirred for 3 h under cooling. Saturated aqueous solution of ammoniumchloride (15 mL) was added and the mixture was extracted with ether(3×10 mL). Combined ethereal solutions were dried with anhydrousmagnesium sulfate and evaporated in vacuo yielding the title acid as afoam.

Yield: 102 mg (76%).

M.p.:

(foam).

R_(F) (SiO₂, chloroform/methanol 9:1) 0.10.

A solution of L-lysine (29.9 mg, 0.205 mmol) in distilled water (0.5 mL)was added to a solution of the above acid (102 mg, 0.205 mmol) in drytetrahydrofuran (7 mL). The resulting solution was stirred for 10 min,acetonitrile (50 mL) was added and the mixture was stirred for 2 h. Theformed solid was filtered, washed with ether (2×30 mL) and driedyielding L-lysinate of the title acid.

Yield: 55.8 mg (42%).

M.p.: 162-180° C. (amorphous).

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.48-7.15 (m, 9H); 6.61-6.50(m, 3H); 6.34 (t, J=7.1 Hz, 1H); 4.42 (d, J=6.4 Hz, 2H); 4.12 (s, 2H);3.58 (m, 4H); 3.49 (s, 2H); 3.38-3.08 (m, ˜5H); 2.70 (bs, 2H); 2.08 (s,˜3H); 1.16-1.75 (m, ˜6H).

(4-Hydroxy-2-methylphenoxy)acetic Acid Methyl Ester

Potassium carbonate (34.4 g, 0.250 mol) and solution of methylbromoacetate (16.1 ml, 0.175 mol) in butanone (20 ml) were added to asolution of 4-hydroxy-3-methylacetophenone (25 g, 0.166 mol) in butanone(180 ml) and the mixture was refluxed for 1 h. After cooling to ambienttemperature a white precipitated was filtered off and the filtrateevaporated in vacuo. The resulting solid was recrystallized bydissolving it in a mixture of hexanes/diethyl ether/dichloromethane(120:120:50 ml) and concentrating in vacuo.(4-Acetyl-2-methylphenoxy)acetic acid methyl ester was filtered andwashed with hexanes (50 mL).

Yield: 35.0 g (95%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1) 0.75.

¹H NMR spectrum (200 MHz, CDCl₃, δ_(H)): 7.80-7.76 (m, 2H); 6.70 (d,J=9.0 Hz, 1H); 4.74 (s, 2H); 3.82 (s, 3H); 2.55 (s, 3H); 2.33 (s, 3H).

To a solution of the above ester (33.0 g, 0.148 mol) andp-toluenesulfonic acid monohydrate (0.281 g, 0.00148 mol) indichloromethane (50 ml) a solution of 3-chloroperoxybenzoic acid (53.1g, 0.237 mol; 77% in water) in dichloromethane was added (300 ml, driedover magnesium sulfate prior to addition). The mixture was stirred atambient temperature for 20 h, a solution of sodium sulfite (1 M, 150 ml)was added and the two-phase mixture stirred for 20 min. Then a solutionof sodium carbonate (2 M, 150 ml) was added and heterogeneous mixturewas vigorously stirred for next 10 min. The organic layer was separatedand the aqueous layer was extracted with dichloromethane (50 ml). Thecombined organic layers were washed with 10% solution of sodiumcarbonate (2×200 ml) and brine (300 ml). The organic solution was driedwith anhydrous magnesium sulfate and its evaporation yielded(4-acetoxy-2-methyl-phenoxy)acetic acid methyl ester as yellowish solid.

Yield: 32.9 g (93%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1) 0.80.

¹H NMR spectrum (200 MHz, CDCl₃, δ_(H)): 6.90 (m, 2H); 6.68 (d, J=8.6,1H); 4.64 (s, 2H); 3.80 (s, 3H); 2.28 (s, 6H).

A mixture of the above ester (32.9 g, 0.138 mol) and sodium methoxide(0.746 g, 0.0138 mol) in anhydrous methanol (250 ml) was stirred for 24h. The mixture was evaporated to dryness and a solid residue wasdissolved in ethyl acetate (200 ml). The turbid mixture was filtered andthe filtrate was washed with saturated aqueous solution of sodiumhydrogen carbonate (2×150 ml) and brine (200 ml). The organic solutionwas dried over anhydrous magnesium sulfate and evaporated in vacuo. Thecrude product was recrystallized from ethyl acetate/hexanes yielding thetitle compound as off-white crystals.

Yield: 24.0 g (89%).

R_(F) (SiO₂, dichloromethane/methanol 99:1) 0.30.

¹H NMR spectrum (200 MHz, CDCl₃, δ_(H)): 6.66-6.58 (m, 3H); 4.76 (s,1H); 4.59 (s, 2H); 3.80 (s, 3H); 2.25 (s, 3H), 2.19 (s, 3H).

Example 3(Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]aceticAcid

To a degassed solution of 4-bromotoluene (4.27 g, 25 mmol) intetrahydrofuran (30 mL) was added in the following order: copper(I)iodide (143 mg, 0.75 mol), tetrakis(triphenylphosphine)palladium (0.85g, 7.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.55 g, 30 mmol).The resulting mixture was degassed one more time, cooled in an ice bathand a solution of propargyl alcohol (1.68 g, 30 mmol) in tetrahydrofuran(5 mL) was added over period of 10 min. The reaction mixture was slowlyheated up to 55° C. and then stirred at this temperature for 20 h. Thismixture was then cooled to ambient temperature, diluted with ether (150mL) and water (50 mL) and acidified with 5% hydrochloric acid. Theethereal layer was separated and the aqueous layer was extracted withether (3×30 mL). The combined organic portions were washed with 5%hydrochloric acid (2×30 mL), saturated aqueous solution of sodiumhydrogen carbonate (2×30 mL), dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, chloroform) affording3-(4-methylphenyl)prop-2-yn-1-ol as oil.

Yield: 2.50 g (68%).

R_(F) (SiO₂, chloroform) 0.20.

Sodium methoxide (12.5 mg, 0.225 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (5 mL, 5 mmol) under argon.The mixture was cooled to 0° C. and a solution of the above hydroxyderivative (730 mg, 5 mmol) in tetrahydrofuran (12.5 mL) was added over10 min. The reaction mixture was stirred at 0° C. for 3 h; dry ethylacetate (0.825 mL) was added and the whole mixture was stirred atambient temperature for 15 min. A degassed solution of 1,4-diiodobenzene(2.15 g, 6.5 mmol) in dry tetrahydrofuran (5 mL), anhydrous zincchloride (0.408 g, 3 mmol), tris(dibenzylideneacetone)dipalladiumchloroform complex (0.103 g, 0.1 mmol), and tri(2-furyl)phosphine (92.5mg, 0.4 mmol) were added; the mixture was degassed and then heated at65° C. for 20 h under nitrogen. The suspension was cooled down toambient temperature, methanol (2.5 mL) was added and the mixture wasstirred for additional 1 h. The reaction was diluted with ether (50 mL)and saturated aqueous solution of ammonium chloride (1.25 mL) was added.The mixture was filtered through a paddle of silica gel and the paddlewas thoroughly washed with ether (100 mL). The solvents were evaporatedand the residue was separated by flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 4:1) affording(Z)-3-(4-iodophenyl)-3-(4-methylphenyl)prop-2-en-1-ol as solidifyingoil.

Yield: 610 mg (35%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1) 0.30.

The above allyl alcohol (420 mg, 1.2 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.259 mg, 1.32 mmol; example 2) andtriphenylphosphine (378 mg, 1.44 mmol) were dissolved in a mixture ofanhydrous toluene (20 mL) and tetrahydrofuran (7 mL). The solution wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.28 mL, 1.44 mmol) in anhydroustetrahydrofuran (2.5 mL) was added dropwise over 10 min. The reactionmixture was allowed to warm up to the ambient temperature with the bathand then was stirred for 48 h. The solvents were evaporated in vacuo andthe residue was submitted to flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 4:1) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-2-methylphenoxy}-acetateas solidifying yellow oil.

Yield: 520 mg (82%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1) 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, 2H); 6.93-7.11 (m,6H); 6.55-6.68 (m, 3H); 6.27 (t, J=7.1 Hz, 1H); 4.58 (s, 2H); 4.47 (d,J=6.6 Hz, 2H); 3.79 (s, 3H); 2.34 (s, 3H); 2.25 (s, 3H).

A solution of the above ester (480 mg, 0.908 mmol) in a mixture oftetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed andN-propargylmorpholine (237 mg, 1.89 mmol) was added under argonatmosphere. The solution was cooled,tetrakis(triphenylphosphine)palladium (84 mg, 0.073 mmol) and copper(I)iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture wasstirred at ambient temperature for 6 h and then left to stand overnight.The mixture was evaporated in vacuo; the residue was dissolved indichloromethane (20 mL) and the formed solution was washed with water(2×10 mL). The organic solution was dried with anhydrous magnesiumsulfate and subsequently evaporated in vacuo. The residue was purifiedby flash column chromatography (silica gel Fluka 60, hexanes/ethylacetate 1:1) yielding methyl(Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.

Yield: 252 mg (53%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1) 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.4 Hz, 2H);7.07-7.16 (m, 6H); 6.54-6.67 (m, 3H); 6.26 (t, J=6.7 Hz, 1H); 4.58 (s,2H); 4.48 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.76-3.79 (m, 4H); 3.53 (s,2H); 2.66 (m, 4H); 2.33 (s, 3H); 2.24 (s, 3H).

To a solution of the above ester (233 mg, 0.443 mmol) intetrahydrofuran/methanol mixture (5:1, 12 mL), a solution of lithiumhydroxide monohydrate (28 mg, 0.665 mmol) in distilled water (2 mL) wasadded under cooling to 0° C. The solution was stirred for 1 h undercooling and 1 h under ambient temperature. The solution was diluted withether (30 mL) and saturated solution of ammonium chloride (15 mL). Thephases were separated; the organic layer was washed with water (2×10mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes yielding the title acid as tansolid.

Yield: 114 mg (64%).

M.p. 182-190° C.

R_(F)(SiO₂, chloroform/methanol, 9:1) 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.39-7.06 (m, 8H); 6.66 (m,1H); 6.57 (m, 1H); 6.39 (m, 1H); 6.30 (t, J=7.1 Hz, 1H); 4.55 (s, 2H);4.44 (d, J=6.6 Hz, 2H); 3.82 (bs, 4H); 3.65 (s, 2H); 2.85 (bs, 4H); 2.33(s, 3H); 2.23 (s, 3H).

Example 4(E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]aceticAcid

To a degassed solution of 1-bromo-4-trifluoromethylbenzene (5.62 g, 25mmol) in tetrahydrofuran (25 ml) was added in the following order:copper(I) iodide (143 mg, 0.75 mL),tetrakis(triphenylphosphine)palladium (0.85 g, 7.5 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (4.55 g, 30 mmol). The resultingmixture was degassed one more time, cooled in an ice bath and a solutionof propargyl alcohol (1.68 g, 30 mmol) in tetrahydrofuran (5 mL) wasadded over period of 10 min. The reaction mixture was slowly heated upto 55° C. and then stirred at this temperature for 3 h and then atambient temperature overnight. The mixture was diluted with diethylether (100 mL), washed with water (50 mL), 5% hydrochloric acid (35 mL)and saturated aqueous solution of sodium hydrogen carbonate (30 mL). Theorganic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, dichloromethane) affording3-(4-trifluoromethylphenyl)prop-2-yn-1-ol.

Yield: 4.25 g (90%).

R_(F) (SiO₂, chloroform) 0.25.

Sodium methoxide (12.5 mg, 0.225 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (5 mL, 5 mmol) under argon.The mixture was cooled to 0° C. and a solution of the above alcohol(1.00 g, 5 mmol) in tetrahydrofuran (12.5 mL) was added over 10 min. Thereaction was stirred at 0° C. for 3 h; dry ethyl acetate (0.825 mL) wasadded and the whole mixture was stirred at ambient temperature for 15min. A degassed solution of 1,4-diiodobenzene (2.15 g, 6.5 mmol) in drytetrahydrofuran (5 mL), anhydrous zinc chloride (0.408 g, 3 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.103 g, 0.1mmol), and tri(2-furyl)phosphine (92.5 mg, 0.4 mmol) were added; themixture was degassed and then was heated at 65° C. for 15 h undernitrogen. The suspension was cooled down; methanol (2.5 mL) was addedand the mixture was stirred for additional 1 h. The reaction was dilutedwith ether (50 mL) and saturated aqueous solution of ammonium chloride(1.25 mL) was added. The mixture was filtered through a paddle of silicagel and the paddle was thoroughly washed with ether (100 mL). Thesolvents were evaporated in vacuo and the residue was purified by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1)affording (Z)-3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)prop-2-en-1-olas solidifying oil.

Yield: 815 mg (47%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1) 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (m, 2H); 7.54 (m, 2H);7.33 (m, 2H); 6.90 (m, 2H); 6.30 (t, J=6.8 Hz, 1H); 4.24 (m, 2H).

The above allyl alcohol (810 mg, 2.0 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (431 mg, 2.2 mmol; example 2) andtriphenylphosphine (630 mg, 2.4 mmol) were dissolved in a mixture ofanhydrous toluene (32 mL) and tetrahydrofuran (12 mL). The mixture wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.47 mL, 2.4 mmol) in anhydroustetrahydrofuran (4 mL) was added dropwise during 10 min. The reactionmixture was allowed to warm up to ambient temperature with the bath andthen was stirred for 48 h. The solvents were evaporated in vacuo and theresidue was submitted to flash column chromatography (silica gel Fluka60, hexanes/ethyl acetate 85:15) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]acetateas solidifying yellow oil.

Yield: 880 mg (76%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1) 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=10.5 Hz, 2H); 7.55(d, J=10.5 Hz, 2H); 7.35 (d, J=10.5 Hz, 2H); 6.93 (d, J=10.5 Hz, 2H);6.69-6.55 (m, 3H); 6.37 (t, J=7.1, 1H); 4.59 (s, 2H); 4.51 (d, 2H); 3.79(s, 3H); 2.26 (s, 3H).

A solution of the above ester (375 mg, 0.644 mmol) in the mixture oftetrahydrofuran (5 mL) and triethylamine (5 mL) was degassed and1-propargylpyrazole (123 mg, 1.16 mmol) was added in argon atmosphere.The solution was cooled down; tetrakis(triphenylphosphine)palladium(59.5 mg, 0.052 mmol) and copper(I) iodide (19.6 mg, 0.103 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 48 h.The mixture was evaporated in vacuo and the residue was purified byflash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate7:3) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(pyrazol-1-yl)prop-1-ynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]acetate.

Yield: 340 mg (94%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1) 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.68 (m, 1H); 7.49-7.48 (m,5H); 7.35-7.14 (m, 4H); 6.67-6.54 (m, 3H); 6.37 (t, J=6.7 Hz, 1H); 6.31(m, 1H); 5.20 (s, 2H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.25 (s, 3H).

To a solution of the above ester (330 mg, 0.589 mmol) intetrahydrofuran/methanol mixture (3:5, 8 mL), a solution of lithiumhydroxide monohydrate (37 mg, 0.883 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1 h undercooling and 1 h at ambient temperature. The solution was diluted withchloroform (70 mL), water (10 mL) and saturated aqueous solution ofammonium chloride (15 mL) and the phases were separated. The organiclayer was washed with brine (10 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanesyielding the title acid as tan solid.

Yield: 142 mg (44%).

M.p. 123-125° C.

R_(F) (SiO₂, chloroform/methanol 4:1) 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.67 (m, 1H); 7.58-7.49 (m,5H); 7.36-7.11 (m, ˜4H); 6.66-6.50 (m, 3H); 6.37 (t, J=6.6 Hz, 1H); 6.33(m, 1H); 5.22 (s, 2H); 4.60 (s, 2H); 4.50 (d, J=6.7 Hz, 2H); 2.36 (s,1H); 2.24 (s, 3H).

Example 5(E)-[2-Methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]aceticAcid

A solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]acetate(370 mg, 0.636 mmol; example 4) in a mixture of tetrahydrofuran (5 mL)and triethylamine (5 mL) was degassed and 2-ethynylpyridine (118 mg,1.144 mmol) was added under argon atmosphere. The solution was cooled;tetrakis(triphenylphosphine)palladium (59.0 mg, 0.051 mmol) andcopper(I) iodide (19.3 mg, 0.102 mmol) were added. The reaction mixturewas stirred at ambient temperature for 48 h. The mixture was evaporatedin vacuo and the residue was dissolved in dichloromethane (60 mL). Thesolution was washed with water (2×20 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3)yielding methyl(E)-[2-methyl-4-[3-[4-(pyridin-2-ylethynyl)phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate.

Yield: 344 mg (94%).

R_(F) (SiO₂, hexanes/ethyl acetate 65:35) 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.64 (bs, 1H); 7.73-7.54 (m,6H); 7.38-7.18 (m, ˜5H); 6.69-6.40 (m, 3H); 6.38 (t, J=6.7 Hz, 1H); 4.58(s, 2H); 4.55 (d, J=6.7 Hz, 2H); 3.78 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (330 mg, 0.575 mmol) intetrahydrofuran/methanol mixture (5:1, 18 mL), a solution of lithiumhydroxide monohydrate (48.3 mg, 1.15 mmol) in distilled water (3 mL) wasadded under cooling to 0° C. The solution was stirred for 1 h undercooling and 1 h under ambient temperature. The reaction mixture wasacidified with glacial acetic acid (66 L, 1.15 mmol) and diluted withchloroform (50 mL); the phases were separated and the organic layer waswashed with water (10 mL), brine (10 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanesyielding the title acid as solid.

Yield: 255 mg (79%).

M.p. 161-165° C.

R_(F) (SiO₂, chloroform/methanol 4:1) 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.67 (bd, J=4.4 Hz, 1H); 7.77(dt, J=7.7 and 1.4 Hz, 1H); 7.55 (m, 5H); 7.37-7.09 (m, 5H); 6.55 (m,2H); 6.48 (m, 1H); 6.40 (t, J=6.7 Hz, 1H); 4.63 (s, 2H); 4.50 (d, J=6.8Hz, 2H); 2.25 (s, 1H).

Example 6(Z)-[4-[3-(4-Chlorophenyl)-3-[4-(4-methylphenylethynyl)phenyl]allyloxy]-2-methylphenoxy]-aceticAcid

Sodium methoxide (0.02 g, 0.37 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (8 mL, 8 mmol) undernitrogen. The mixture was cooled to 0° C. and a solution of3-(4-bromophenyl)prop-2-yn-1-ol (1.69 g, 8.01 mmol; prepared asdescribed in experimental part of the synthesis of compound VUFB-21041)in tetrahydrofuran (8 mL) was added over 30 min. The reaction wasstirred at 0° C. for 3.5 h; dry ethyl acetate (2.40 mL, 24.6 mmol) wasadded and the whole mixture was stirred at ambient temperature for 15min. A degassed solution of 1-chloro-4-iodobenzene (2.01 g, 8.43 mmol)in dry tetrahydrofuran (5 mL), anhydrous zinc chloride (0.66 g, 4.84mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.18 g,0.17 mmol), and tri-2-furyl phosphine (0.20 g, 0.86 mmol) were added;the mixture was degassed and then was heated at 65° C. for 18 h undernitrogen. The suspension was cooled down; methanol (4 mL) was added andthe mixture was stirred for additional 1 h. The reaction was dilutedwith ether (40 mL) and saturated aqueous solution of ammonium chloride(2 mL) was added. The mixture was filtered through a paddle of silicagel and the paddle was thoroughly washed with ether (100 mL). Solventswere evaporated and the residue was separated by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 6:1)affording (E)-[3-(4-bromophenyl)-3-(4-chlorophenyl)]allyl alcohol assolidifying oil.

Yield: 1.45 g (56%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1) 0.20.

The above allyl alcohol (1.45 g, 4.44 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.96 g, 4.89 mmol; compoundVUFB-21004) and triphenylphosphine (1.35 g, 5.15 mmol) were dissolved ina mixture of anhydrous toluene (75 mL) and tetrahydrofuran (25 mL). Themixture was cooled to 0° C., kept under nitrogen and a degassed solutionof diisopropyl azodicarboxylate (1.00 mL, 5.04 mmol) in anhydroustetrahydrofuran (10 mL) was added dropwise during 15 min. The reactionmixture was allowed to warm up the ambient temperature with the bath andthen was stirred overnight. The solvents were evaporated in vacuo andthe residue was submitted to flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 12:1) affording methyl(E)-[4-[3-(4-bromophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenoxy]acetateas solidifying yellow oil.

Yield: 1.94 g (87%).

R_(F) (SiO₂, hexanes/ethyl acetate 9:1) 0.15.

In nitrogen atmosphere, bis(benzonitrile)palladium(II) chloride (14.6mg, 0.038 mmol), copper(I) iodide (12.1 mg, 0.064 mmol) and 0.15 Msolution of tri(tert-butyl)phosphine in cyclohexane (0.60 mL, 0.090mmol) were added to a degassed solution of methyl(E)-[4-[3-(4-bromophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenoxy]acetate(383 mg, 0.763 mmol), 4-ethynyltoluene (115 mg, 0.990 mmol) anddiisopropyl amine (0.50 mL, 3.57 mmol) in dry tetrahydrofuran (6 mL). Inatmosphere of nitrogen, the reaction mixture was stirred at 60° C. for 4h, cooled down and evaporated in vacuo. The residue was purified byflash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate12:1) yielding methyl(Z)-[4-[3-(4-chlorophenyl)-3-[4-(4-methylphenylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetateas brownish oil.

Yield: 315 mg (77%).

R_(F) (SiO₂, hexanes/ethyl acetate 9:1) 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.37 (m, 6H); 7.23-7.13(m, ˜6H); 6.69-6.55 (m, 3H); 6.35 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.50(d, J=6.6 Hz, 2H); 3.79 (s, 3H); 2.37 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (232 mg, 0.432 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (26 mg, 0.620 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 60 min undercooling, glacial acetic acid (0.05 mL, 0.874 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (20 mL) and water (15 mL); the phases were separated and theaqueous phase was extracted with ether (3×10 mL). The combined organiclayers were washed with water (2×10 mL) and brine (2×10 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with dichloromethane/hexanes mixture (1:10, 11 mL) yieldingthe title acid as grayish solid.

Yield: 183 mg (81%).

M.p. 157-175° C. (amorphous).

R_(F) (SiO₂, dichloromethane/methanol 90:10) 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46-7.37 (m, 6H); 7.23-7.14(m, 6H); 6.68-6.57 (m, 3H); 6.35 (t, J=6.6 Hz, 1H); 4.62 (s, 2H); 4.51(d, J=6.6 Hz, 2H); 2.37 (s, 3H); 2.25 (s, 3H).

Example 7(E)-[4-[3-(4-Chlorophenyl)-3-[4-(3,3-dimethylbutynyl)phenyl]allyloxy]-2-methylphenoxy]aceticAcid

A solution of 1-chloro-4-iodobenzene (23.9 g, 100.0 mmol) in drytetrahydrofuran (100 mL) was degassed and copper(I)iodide (570 mg, 3.0mmol), tetrakis(triphenylphosphine)palladium (3.4 g, 3.0 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (18.2 g, 120.0 mmol) were added. Thereaction solution was degassed again and propargyl alcohol (6.7 g, 120.0mmol) was added under inert atmosphere at ambient temperature. Thereaction mixture was stirred (initially under cooling with ice water)for 24 h, then treated with water (20 mL) and acidified with 2 Mhydrochloric acid (20 mL). The organic phase was separated and theaqueous phase was extracted with ether (4×30 mL). The combined organicphases were dried with anhydrous magnesium sulfate and concentrated invacuo yielding brown solid. The residue was purified by columnchromatography (silica gel Fluka 60, chloroform) yielding3-(4-chlorophenyl)prop-2-yn-1-ol.

Yield: 8.35 g (50%).

M.p.: 75.5-77.5° C. (hexane).

R_(F) (SiO₂, hexane/ethyl acetate 90:10): 0.10.

Sodium methoxide (0.05 g, 0.9 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (20 mL, 20 mmol). The mixture wascooled to 0° C., and a solution of the above alcohol (3.35 g, 20.1 mmol)in tetrahydrofuran (30 mL) was slowly added.

The reaction mixture was stirred at 0° C. for 1.5 h and at ambienttemperature for 1.5 h. Ethyl acetate (3.3 mL, 34 mmol) was added at 0°C., and the mixture was stirred for 20 min without cooling.1,4-Diiodobenzene (6.6 g, 20 mmol), anhydrous zinc chloride (1.64 g, 12mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.41 g,0.4 mmol), and tri-(2-furyl)phosphine (0.37 g, 1.6 mmol) were added; themixture was evacuated and kept under nitrogen. Reaction mixture washeated at 65° C. for 16 h, and then cooled down. Methanol (10 mL) wasadded and the mixture was stirred for additional 1 h. The reactionsuspension was diluted with ether (150 mL), and saturated aqueoussolution of ammonium chloride (5 mL) was added. The mixture was filteredthrough a paddle of silica gel and the solid phase was thoroughly washedwith ether. Solvents were evaporated in vacuo and the residue wassubmitted to column chromatography (silica gel Fluka 60;benzene-chloroform) affording(Z)-[3-(4-chlorophenyl)-3-(4-iodophenyl)]allyl alcohol as light brownsolid.

Yield: 3.5 g (49%).

M.p.: 79-84° C.

R_(F) (SiO₂, chloroform/ether 2:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.7 Hz, 2H); 7.26(d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H); 6.90 (d, J=8.7 Hz, 2H); 6.22(t, J=6.9 Hz, 1H); 4.20 (d, J=6.9 Hz, 2H); 1.55 (s, 1H).

The above allyl alcohol (3.45 g, 9.7 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.96 g, 10 mmol; example 2) andtriphenylphosphine (2.9 g, 11 mmol) were dissolved in a mixture ofanhydrous toluene (50 mL) and tetrahydrofuran (25 mL). The mixture wascooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate(2.3 g, 10.8 mmol) was added dropwise. The reaction mixture was stirredat 0° C. for 3 h and then at ambient temperature for 16 h. The solventswere evaporated in vacuo and the residue was submitted to columnchromatography (silica gel Fluka 60, benzene) affording methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetateas solid.

Yield: 3.1 g (58%).

M.p.: 89-92° C.

R_(F) (SiO₂, chloroform): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=8.4 Hz, 2H); 7.26(d, J=8.7 Hz, 2H); 7.16 (d, J=8.7 Hz, 2H); 6.93 (d, J=8.4 Hz, 2H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.57 (dd, J=8.7 and 2.7 Hz);6.29 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.26 (s, 3H).

t-Butylacetylene (220 mg, 2.7 mmol) was added under nitrogen atmosphereto a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate(500 mg, 0.91 mmol) in a mixture of tetrahydrofuran (8 mL) andtriethylamine (8 mL) The solution was cooled,tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I)iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture wasstirred at ambient temperature for 72 h, diluted with benzene (100 mL)and washed with water (2×50 mL). The organic solution was dried withanhydrous magnesium sulfate and subsequently evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 1:1) and recrystallized from ethanol yieldingmethylE)-[4-[3-(4-chlorophenyl)-3-[4-(3,3-dimethylbutynyl)phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 330 mg (72%).

M.p.: 115-116.5° C. (ethanol).

R_(F) (SiO₂, cyclohexane/tetrahydrofuran 9:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.4 Hz, 2H); 7.25(d, J=8.7 Hz, 2H); 7.15 (d, J=8.7 Hz, 2H); 7.09 (d, J=8.4 Hz, 2H); 6.66(d, J=2.7 Hz, 1H); 6.61 (d, J=8.7 Hz, 1H); 6.55 (dd, J=8.7 and 2.7 Hz);6.26 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.24 (s, 3H); 1.33 (s, 9H).

The above ester (0.33 g, 0.656 mmol) was dissolved inethanol/tetrahydrofuran mixture (1:1, 30 mL); a solution of lithiumhydroxide monohydrate (0.08 g, 1.9 mmol) in water (3 mL) was added andthe mixture was left to stand for 72 h. The solvents were evaporated invacuo; the residue was diluted with water (25 mL) and acidified withacetic acid (0.5 mL). The product was filtered off and dried in the airyielding the title compound.

Yield: 0.30 g (94%).

M.p.: 144-147° C.

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.4 Hz, 2H); 7.24(d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H); 7.09 (d, J=8.4 Hz, 2H); 6.62(m, 2H); 6.54 (dd, J=8.5 and 3.0 Hz); 6.25 (t, J=6.6 Hz, 1H); 4.56 (s,2H); 4.47 (d, J=6.6 Hz, 2H); 2.21 (s, 3H); 1.32 (s, 9H).

Example 8 (E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetic Acid

N,N-Dimethylpropargylamine (200 mg, 2.4 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-iodoophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenoxy]acetate(500 mg, 0.91 mmol; example 7) in a mixture of tetrahydrofuran (8 mL)and triethylamine (8 mL) The solution was cooled,tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I)iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture wasstirred at ambient temperature for 48 h, dissolved in benzene (100 mL)and washed with water (2×50 mL). The organic solution was dried withanhydrous potassium carbonate and subsequently evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,benzene-chloroform/ether 2:1) yielding(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 400 mg (87%).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.1 Hz, 2H); 7.25(d, J=8.7 Hz, 2H); 7.16 (d, J=8.7 Hz, 2H); 7.12 (d, J=8.1 Hz, 2H); 6.66(d, J=2.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.56 (dd, J=8.7 and 2.7 Hz);6.27 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.78 (s,3H); 3.49 (s, 2H); 2.38 (s, 6H); 2.24 (s, 3H).

The above ester (0.40 g, 0.794 mmol) was dissolved in ethanol (50 mL), asolution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 48 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.5 mL) and extracted with ethylacetate (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas purified by column chromatography (silica gel Fluka 60,chloroform/ethanol/ammonia 1:1:0.05) affording oil which was trituratedwith hexane yielding the title compound as amorphous solid.

Yield: 0.34 g (87.5%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.05.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.25(d, J=8.4 Hz, 2H); 7.15 (m, 4H); 6.64 (m, 2H); 6.48 (dd, J=8.7 and 2.7Hz); 6.31 (t, J=6.6 Hz, 1H); 4.48 (s, 2H); 4.42 (d, J=6.6 Hz, 2H); 3.86(s, 2H); 2.64 (s, 6H); 2.24 (s, 3H).

Example 9(E)-[4-[3-(4-Chlorophenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]aceticAcid

2-Ethynylpyridine (250 mg, 2.42 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]-acetate(500 mg, 0.91 mmol; example 7) in a mixture of tetrahydrofuran (8 mL)and triethylamine (8 mL) The solution was cooled,tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I)iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture wasstirred at ambient temperature for 72 h, diluted with benzene (100 mL)and washed with water (2×50 mL). The organic solution was dried withanhydrous potassium carbonate and subsequently evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,benzene-chloroform/ether 2:1) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 400 mg (84%).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.70.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.63 (d, J=4.5 Hz, 1H); 7.70(dt, 1H); 7.63 (d, J=8.3 Hz, 2H); 7.56 (d, J=7.8 Hz, 1H); 7.27 (m, 3H);7.20 (m, 4H); 6.68 (d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd,J=8.8 and 2.7 Hz); 6.30 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7Hz, 2H); 3.78 (s, 3H); 2.25 (s, 3H).

The above ester (0.30 g, 0.57 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.08 g, 1.9 mmol) in water (4mL) was added and the mixture was left to stand for 72 h. The solventswere evaporated in vacuo, the residue was diluted with water (25 mL),acidified with acetic acid (0.5 mL) and extracted with chloroform (2×50mL). The organic solution was dried with anhydrous potassium carbonateand subsequently evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, ethyl acetate) affording oil whichwas triturated with hexane yielding the title compound as amorphoussolid.

Yield: 0.25 g (86%).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.69 (d, J=4.5 Hz, 1H); 7.75(dt, 1H); 7.55 (m, 3H); 7.31 (m, 1H); 7.26 (m, 2H); 7.15 (m, 4H); 6.66(m, 2H); 6.57 (dd, J=8.9 and 3.0 Hz); 6.29 (t, J=6.8 Hz, 1H); 4.62 (s,2H); 4.47 (d, J=6.8 Hz, 2H); 2.24 (s, 3H).

Example 10(E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

A solution of 4-fluoro-1-iodobenzene (11.0 g, 50.0 mmol) in anhydroustetrahydrofuran (90 mL) was degassed and copper(I) iodide (0.29 g, 1.5mmol), tetrakis(triphenylphosphine)palladium (1.75 g, 1.5 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (9.25 g, 60.0 mmol) were added. Thereaction solution was degassed again and propargyl alcohol (3.5 mL, 60.0mmol) was added dropwise under inert atmosphere at ambient temperature.The obtained yellow suspension was stirred at ambient temperatureovernight, then treated with brine (10 mL) and acidified with 2 Mhydrochloric acid to pH-2. The phases were separated and the aqueousphase was extracted with ether (4×50 mL). The combined organic phaseswere washed with water (3×30 mL) and brine (2×30 mL), dried overanhydrous magnesium sulfate and concentrated in vacuo yielding brownsolid. The residue was purified by column chromatography (silica gelFluka 60, hexanes/ethyl acetate 90:10) and the obtained light yellowsolid was crystallized from hexane yielding3-(4-fluorophenyl)prop-2-yn-1-ol as light yellow needles.

Yield: 6.2 g (83%).

M.p. 32-33° C. (hexane).

R_(F) (hexanes/ethyl acetate 80:20) 0.30.

Sodium methoxide (0.05 g, 0.9 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (20 mL, 20 mmol). The mixture wascooled to 0° C., and a solution of the above alcohol (3.0 g, 20.0 mmol)in tetrahydrofuran (30 mL) was slowly added. The reaction mixture wasstirred at 0° C. for 3 h, ethyl acetate (5.5 mL, 60.1 mmol) was addedand the mixture was stirred for further 10 min without cooling.1,4-Diiodobenzene (6.3 g, 19.0 mmol), anhydrous zinc chloride (1.65 g,12.0 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex(0.42 g, 0.4 mmol) were added; the mixture was evacuated and kept undernitrogen. A solution of tri(2-furyl)phosphine (0.37 g, 1.6 mmol) wasadded and the mixture was heated at 50° C. overnight under nitrogen.Methanol (10 mL) was added and the mixture was stirred for additional 1h. The reaction mixture was diluted with ether (100 mL) and saturatedaqueous solution of ammonium chloride (5 mL) was added. The mixture wasfiltered through a paddle of silica gel, evaporated in vacuo and theresidue was purified by column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 90:10) affording(Z)-3-(4-fluorophenyl)-3-(4-iodopheny)lallyl alcohol.

Yield: 3.1 g (43%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20) 0.25.

The above allyl alcohol (3.0 g, 8.5 mmol) was dissolved in anhydroustetrahydrofuran (50 mL) and anhydrous toluene (150 mL), methyl(4-hydroxy-2-methylphenoxy) acetate (1.83 g, 9.3 mmol; example 2) andtriphenylphosphine (2.7 g, 10.3 mmol) were added to the solution. Themixture was evacuated and cooled to 0° C. under nitrogen. A degassedsolution of diisopropyl azodicarboxylate (2.0 mL, 10.3 mmol) inanhydrous tetrahydrofuran (20 mL) was added dropwise during 30 min andthe reaction mixture was allowed to warm up to the ambient temperatureand then was stirred overnight. The solvents were evaporated in vacuoand the residue was submitted to flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 90:10) affording methyl(Z)-[4-[3-(4-fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetateas solidifying light yellow oil.

Yield: 3.0 g (67%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20) 0.55.

Methyl(Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.75 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL);anhydrous triethylamine (20 mL) and a solution of 4-propargylmorpholine(190 mg, 1.51 mmol) in anhydrous tetrahydrofuran (2 mL) were added. Thesolution was degassed and copper(I) iodide (23 mg, 0.12 mmol) andtetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were addedunder nitrogen atmosphere. The mixture was stirred at ambienttemperature overnight, the resulting suspension was filtered through apaddle of silica gel and silica gel was thoroughly washed with ethylacetate. Filtrate was washed with water (2×30 mL) and brine (2×30 mL),dried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was purified using column chromatography (silica gel Fluka 60,chloroform saturated with ammonia/methanol 99:1) yielding(E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]-phenyl]allyloxy]-2-methyl-phenoxy]acetateas yellow oil.

Yield: 370 mg (95%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 99:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H);7.23-7.13 (m, 4H); 6.98 (t, J=8.6 Hz, 2H); 6.68-6.55 (m, 3H); 6.24 (t,J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79-3.75 (m, 5H);3.54 (s, 2H); 2.68-2.56 (m, 6H); 2.25 (s, 3H).

To a solution of the above ester (370 mg, 0.718 mmol) intetrahydrofuran/methanol mixture (5:2, 7 mL), a solution of lithiumhydroxide monohydrate (70 mg, 1.44 mmol) in distilled water (2.5 mL) wasadded and the solution was stirred for 60 min at ambient temperature.The mixture was neutralized with 2 M hydrochloric acid and diluted withether (50 mL) and water (20 mL). The phases were separated and theaqueous layer was extracted with ether (2×15 mL). The combined organiclayers were washed with water (2×15 mL) and brine (3×15 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastreated with hexane giving the title acid as brownish crystals.

Yield: 260 mg (72%).

M.p.: 145-171° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.25.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.50 (d, J=8.2 Hz, 2H);7.25-7.14 (m, 6H); 6.72-6.69 (m, 2H); 6.61 (dm, J=8.9 and 2.9 Hz, 2H);6.23 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.46 (d, J=6.7 Hz, 2H); 3.63-3.60(m, 4H); 3.53 (s, 2H); 2.54-2.53 (m, 4H); 2.14 (s, 3H).

Example 11(E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(methylsulfanyl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Methyl(Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.75 mmol; example 10) was dissolved in anhydroustetrahydrofuran (10 mL); anhydrous triethylamine (20 mL) and a solutionof 3-(methylsulfanyl)propyne (130 mg, 1.51 mmol) in anhydroustetrahydrofuran (2 mL) were added. Resulting solution was degassed andcopper(I) iodide (23 mg, 0.12 mmol) andtetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol) were addedunder nitrogen atmosphere. Reaction mixture was stirred at ambienttemperature overnight, the resulting suspension was filtered through apaddle of silica gel and silica gel was thoroughly washed with ethylacetate. The filtrate was evaporated in vacuo; the obtained residue wasdissolved in dichloromethane and the solution was washed with water(2×30 mL) and brine (2×30 mL), dried over anhydrous magnesium sulfateand evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 90:10)yielding methyl(E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(methylsulfanyl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 310 mg (84%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.2 Hz, 2H);7.23-7.12 (m, 4H); 7.00-6.95 (m, 2H); 6.67-6.54 (m, 3H); 6.24 (t, J=6.7Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.49 (s,2H); 2.31 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (300 mg, 0.611 mmol) in tetrahydrofuran(5 mL) and methanol (2 mL), a solution of lithium hydroxide monohydrate(60 mg, 1.22 mmol) in distilled water (2 mL) was added. The solution wasstirred for 60 min at ambient temperature and subsequently neutralizedwith 2 M hydrochloric acid. The mixture was diluted with ether (50 mL)and water (20 mL); the phases were separated and the aqueous layer wasextracted with ether (2×15 mL). The combined organic layers were washedwith water (2×15 mL) and brine (3×15 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo.

The residue was treated with hexane giving the title acid as brownishcrystals.

Yield: 260 mg (72%).

M.p.: 145-171° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.25.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.49 (d, J=8.1 Hz, 2H);7.24-7.16 (m, 6H); 6.72-6.69 (m, 2H); 6.63-6.59 (m, 1H); 6.30 (t, J=6.7Hz, 1H); 4.59 (s, 2H); 4.46 (d, J=6.7 Hz, 2H); 3.62 (s, 2H); 2.24 (s,3H); 2.14 (s, 3H).

Example 12(E)-[4-[3-(4-Fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]aceticAcid

Methyl(Z)-[4-[3-(4-fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.75 mmol; example 10) was dissolved in anhydroustetrahydrofuran (10 mL). Anhydrous triethylamine (20 mL) and a solutionof 2-ethynylpyridine (155 mg, 1.50 mmol) in anhydrous tetrahydrofuran (2mL) were added. The solution was degassed and copper(I) iodide (23 mg,0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06 mmol)were added. A mixture was stirred at ambient temperature under nitrogenatmosphere overnight; the resulting suspension was filtered through apaddle of silica gel and silica gel was thoroughly washed with ethylacetate. The obtained filtrate was evaporated in vacuo and the residuewas dissolved in ethyl acetate (50 mL). The solution was washed withwater (2×30 mL) and brine (2×30 mL), dried over anhydrous magnesiumsulfate and evaporated in vacuo.

The residue was purified using column chromatography (silica gel Fluka60, hexanes/ethyl acetate 90:10) yielding methyl(E)-[4-[3-(4-fluorophenyl)-3-[4-[(pyridin-2-yl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas orange oil.

Yield: 310 mg (81%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20): 0.65.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.64 (d, J=4.4 Hz, 1H);7.73-7.68 (m, 1H); 7.69-7.63 (d, J=8.3 Hz, 2H); 7.55 (d, J=8.3 Hz, 1H);7.25-7.19 (m, 5H); 6.97 (t, J=8.7 Hz, 2H); 6.69-6.56 (m, 3H); 6.26 (t,J=6.7 Hz, 1H); 4.59 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 2.25(s, 3H).

To a solution of the above ester (300 mg, 0.591 mmol) intetrahydrofuran/methanol mixture (5:2, 7 mL), a solution of lithiumhydroxide monohydrate (60 mg, 1.22 mmol) in distilled water (2.0 mL) wasadded and reaction mixture was stirred for 60 min at ambienttemperature. The solution was neutralized with 2 M hydrochloric acid anddiluted with ether (50 mL) and water (20 mL). Phases were separated andthe aqueous layer was extracted with ether (2×10 mL). The combinedorganic layers were washed with water (2×15 mL) and brine (3×15 mL),dried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was treated with a mixture of hexane and dichloromethane (10:1,7 mL) giving the title acid as grayish crystals.

Yield: 240 mg (82%).

M.p.: 90-95° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.30.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 8.62 (d, J=4.8 Hz, 1H); 7.87(dt, J=7.7 and 1.8 Hz, 1H); 7.69-7.65 (m, 3H); 7.45-7.41 (m, 1H);7.29-7.16 (m, 6H); 6.72-6.69 (m, 2H); 6.64-6.60 (m, 1H); 6.33 (t, J=6.7Hz, 1H); 4.57 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 2.14 (s, 3H).

Example 13(E)-[4-[3-[4-[3-(Dimethylamino)propynyl)phenyl]-3-(4-fluorophenyl)allyloxy]-2-methyl-phenoxy]aceticAcid

Methyl(Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.75 mmol; example 10 was dissolved in a mixture of anhydroustetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). Thesolution was degassed and a solution of N,N-dimethylpropargylamine (125mg, 1.50 mmol) in anhydrous tetrahydrofuran (2 mL) was added under inertatmosphere. The resulting solution was degassed once more, copper(I)iodide (23 mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70mg, 0.06 mmol) were added and the mixture was degassed again. Thereaction mixture was stirred at ambient temperature overnight and theresulting suspension was filtered through a paddle of silica gel. Silicagel was washed thoroughly with ethyl acetate; the filtrate wasevaporated in vacuo and the residue was dissolved in dichloromethane (50mL). The solution was washed with water (2×30 mL) and brine (2×30 mL),dried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,dichloromethane/methanol 99:1) yielding methyl(E)-[4-[3-[4-[3-(dimethylamino)propynyl)-phenyl]-3-(4-fluorophenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 320 mg (87%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.3 Hz, 2H);7.23-7.12 (m, 4H); 7.00-6.95 (m, 2H); 6.68-6.55 (m, 3H); 6.24 (t, J=6.7Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.50 (s,2H); 2.39 (s, 6H); 2.25 (s, 3H).

To a solution of the above ester (300 mg, 0.615 mmol) in tetrahydrofuran(5 mL) and methanol (2 mL), a solution of lithium hydroxide monohydrate(60 mg, 1.22 mmol) in distilled water (2 mL) was added. The solution wasstirred for 60 min at ambient temperature, neutralized with saturatedaqueous solution of ammonium chloride (10 mL) and extracted with ether(3×30 mL) and dichloromethane (3×30 mL). The combined organic extractswere washed with saturated aqueous solution of ammonium chloride (2×10mL), dried over anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was treated with of hexanes/dichloromethane mixture (10:1, 5 mL)giving the title acid as yellowish crystals.

Yield: 165 mg (57%).

M.p.: 115-143° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.10.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.49 (d, J=8.2 Hz, 2H);7.27-7.14 (m, 6H); 6.70-6.68 (m, 2H); 6.62-6.58 (m, 1H); 6.23 (t, J=6.7Hz, 1H); 4.54 (s, 2H); 4.46 (d, J=6.7 Hz, 2H); 3.49 (s, 2H); 2.26 (s,6H); 2.13 (s, 3H).

Example 14(E)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Methyl(Z)-[4-[3-(4-Fluorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.75 mmol; example 10) was dissolved in a mixture of anhydroustetrahydrofuran (10 mL) and anhydrous triethylamine (20 mL). Thesolution was degassed and a solution of 1-propargylpyrazol (160 mg, 1.50mmol) in anhydrous tetrahydrofuran (2 mL) was added under inertatmosphere. The resulting solution was degassed and copper(I) iodide (23mg, 0.12 mmol) and tetrakis(triphenylphosphine)palladium (70 mg, 0.06mmol) were added and the mixture was degassed again. The reactionmixture was stirred at ambient temperature overnight; the resultingsuspension was filtered through a paddle of silica gel. Silica gel wasthoroughly washed with ethyl acetate; the filtrate was evaporated andthe residue was dissolved in dichloromethane (30 mL). The solution waswashed with water (2×30 mL) and brine (2×30 mL), dried over anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 80:20)yielding methyl(E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-allyloxy]-2-methyl-phenoxy]acetateas orange oil.

Yield: 270 mg (70%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (d, J=2.3 Hz, 1H); 7.56(d, J=1.7 Hz, 1H); 7.48 (d, J=8.2 Hz, 2H); 7.22-7.14 (m, 4H); 6.98 (t,J=8.7 Hz, 2H); 6.67-6.54 (m, 3H); 6.32 (t, J=2.1 Hz, 1H); 6.25 (t, J=6.7Hz, 1H); 5.20 (s, 2H); 4.58 (s, 2H); 4.47 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.24 (s, 3H).

To a solution of the above ester (250 mg, 0.615 mmol) in tetrahydrofuran(5 mL) and methanol (2 mL), a solution of lithium hydroxide monohydrate(50 mg, 1.22 mmol) in distilled water (2 mL) was added. The solution wasstirred for 2 hours at ambient temperature, neutralized 2 M hydrochloricacid and diluted with ether (30 mL) and water (20 mL). Layers wereseparated and the aqueous layer was extracted with ether (3×30 mL). Thecombined organic extracts were washed with water (2×30 mL) and brine(2×30 mL), dried over anhydrous magnesium sulfate and evaporated invacuo. The residue was treated with hexane/dichloromethane mixture(10:1, 5 mL) giving the title acid as yellowish crystals.

Yield: 130 mg (53%).

M.p.: 35-56° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.20.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.88 (d, J=2.2 Hz, 1H);7.54-7.51 (m, 3H); 7.26-7.13 (m, 6H); 6.72-6.69 (m, 2H); 6.60 (dd, J=8.8and 2.9 Hz, 1H); 6.28-6.23 (m, 2H); 5.32 (s, 2H); 4.59 (s, 2H); 4.45 (d,J=6.7 Hz, 2H); 2.13 (s, 3H).

Example 15(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

A solution of 1-chloro-4-iodobenzene (23.9 g, 100.0 mmol) in drytetrahydrofuran (100 mL) was degassed and copper(I)iodide (570 mg, 3.0mmol), tetrakis(triphenylphosphine)-palladium (3.4 g, 3.0 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (18.2 g, 120.0 mmol) were added. Thereaction solution was degassed again and propargyl alcohol (6.7 g, 120.0mmol) was added under inert atmosphere at ambient temperature. Thereaction mixture was stirred (initially under cooling with ice water)for 24 h, then treated with water (20 mL) and acidified with 2 Mhydrochloric acid (20 mL). The organic phase was separated and theaqueous phase was extracted with ether (4×30 mL). The combined organicphases were dried with anhydrous magnesium sulfate and concentrated invacuo yielding brown solid. The residue was purified by columnchromatography (silica gel Fluka 60, chloroform) yielding3-(4-chlorophenyl)prop-2-yn-1-ol.

Yield: 8.35 g (50%).

M.p.: 75.5-77.5° C. (hexane).

R_(F) (SiO₂, hexane/ethyl acetate 90:10): 0.10.

Sodium methoxide (0.05 g, 0.9 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (20 mL, 20 mmol). The mixture wascooled to 0° C., and a solution of the above alcohol (3.35 g, 20.1 mmol)in tetrahydrofuran (30 mL) was slowly added. The reaction mixture wasstirred at 0° C. for 1.5 h and at ambient temperature for 1.5 h. Ethylacetate (3.3 mL, 34 mmol) was added at 0° C., and the mixture wasstirred for 20 min without cooling. 1,4-Diiodobenzene (6.6 g, 20 mmol),anhydrous zinc chloride (1.64 g, 12 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.41 g, 0.4mmol), and tri-(2-furyl)phosphine (0.37 g, 1.6 mmol) were added; themixture was evacuated and kept under nitrogen. Reaction mixture washeated at 65° C. for 16 h, and then cooled down. Methanol (10 mL) wasadded and the mixture was stirred for additional 1 h. The reactionsuspension was diluted with ether (150 mL), and saturated aqueoussolution of ammonium chloride (5 mL) was added. The mixture was filteredthrough a paddle of silica gel and the solid phase was thoroughly washedwith ether. Solvents were evaporated in vacuo and the residue wassubmitted to column chromatography (silica gel Fluka 60;benzene-chloroform) affording(Z)-[3-(4-chlorophenyl)-3-(4-iodophenyl)]allyl alcohol as light brownsolid.

Yield: 3.5 g (49%).

M.p.: 79-84° C.

R_(F) (SiO₂, chloroform/ether 2:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.7 Hz, 2H); 7.26(d, J=8.8 Hz, 2H); 7.15 (d, J=8.8 Hz, 2H); 6.90 (d, J=8.7 Hz, 2H); 6.22(t, J=6.9 Hz, 1H); 4.20 (d, J=6.9 Hz, 2H); 1.55 (s, 1H).

The above allyl alcohol (3.45 g, 9.7 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.96 g, 10 mmol; example 2) andtriphenylphosphine (2.9 g, 11 mmol) were dissolved in a mixture ofanhydrous toluene (50 mL) and tetrahydrofuran (25 mL). The mixture wascooled to 0° C., kept under nitrogen and diisopropyl azodicarboxylate(2.3 g, 10.8 mmol) was added dropwise. The reaction mixture was stirredat 0° C. for 3 h and then at ambient temperature for 16 h. The solventswere evaporated in vacuo and the residue was submitted to columnchromatography (silica gel Fluka 60, benzene) affording methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetateas solid.

Yield: 3.1 g (58%).

M.p.: 89-92° C.

R_(F) (SiO₂, chloroform): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=8.4 Hz, 2H); 7.26(d, J=8.7 Hz, 2H); 7.16 (d, J=8.7 Hz, 2H); 6.93 (d, J=8.4 Hz, 2H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.57 (dd, J=8.7 and 2.7 Hz);6.29 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.26 (s, 3H).

N-Propargylpyrrolidine (300 mg, 2.75 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate(500 mg, 0.91 mmol) in a mixture of tetrahydrofuran (8 mL) andtriethylamine (8 mL) The solution was cooled,tetrakis(triphenylphosphine)palladium (96 mg, 0.083 mmol) and copper(I)iodide (27.6 mg, 0.145 mmol) were added. The reaction mixture wasstirred at ambient temperature for 72 h, diluted with benzene (100 mL)and the resulting mixture was washed with water (2×50 mL). The organicsolution was dried with anhydrous potassium carbonate and subsequentlyevaporated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, benzene-chloroform/ether 2:1) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]-acetate.

Yield: 350 mg (73%).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.2 Hz, 2H); 7.25(d, J=8.7 Hz, 2H); 7.16 (d, J=8.7 Hz, 2H); 7.12 (d, J=8.2 Hz, 2H); 6.66(d, J=3.0 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.56 (dd, J=8.7 and 3.0 Hz);6.27 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 3.65 (s, 2H); 2.71 (m, 4H); 2.24 (s, 3H); 1.85 (m, 4H).

The above ester (0.31 g, 0.585 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.08 g, 1.9 mmol) in water (4mL) was added and the mixture was left to stand for 72 h. The solventswere evaporated in vacuo; the residue was diluted with water (25 mL),acidified with acetic acid (0.5 mL) and extracted with ethyl acetate(2×50 mL). The organic solution was dried with anhydrous potassiumcarbonate and subsequently evaporated in vacuo. The residue was purifiedby column chromatography (silica gel Fluka 60,chloroform/ethanol/ammonia 1:1:0.05) affording oil which was trituratedwith hexane yielding the title compound as amorphous solid.

Yield: 0.28 g (93%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.05.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.43 (d, J=7.8 Hz, 2H); 7.25(d, J=8.7 Hz, 2H); 7.15 (m, 4H); 6.64 (m, 2H); 6.46 (d, 1H); 6.31 (t,J=7.2 Hz, 1H); 4.48 (s, 2H); 4.41 (d, J=7.2 Hz, 2H); 4.06 (s, 2H); 3.25(bs, 4H); 2.24 (s, 3H); 2.01 (bs, 4H).

Example 16(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

1-Propargylpyrazol (500 mg, 4.7 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate(680 mg, 1.24 mmol; example 15) in a mixture of tetrahydrofuran (10 mL)and triethylamine (10 mL) The solution was cooled,tetrakis(triphenylphosphine)palladium (118 mg, 0.1 mmol) and copper(I)iodide (38 mg, 0.2 mmol) were added. The reaction mixture was stirred atambient temperature for 48 h, diluted with benzene (100 mL) and theresulting mixture was washed with water (2×50 mL). The organic solutionwas dried with anhydrous potassium carbonate and subsequently evaporatedin vacuo. The residue was purified by column chromatography (silica gelFluka 60, benzene-chloroform/ether 2:1) yielding methyl(E)[4-[3-(4-chlorophenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.

Yield: 610 mg (93%).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.75.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (d, J=2.3 Hz, 1H); 7.56(d, J=1.7 Hz, 1H); 7.48 (d, J=8.2 Hz, 2H); 7.26 (d, J=8.6 Hz, 2H); 7.16(m, 4H); 6.66 (d, J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8and 2.8 Hz, 1H); 6.29 (m, 2H); 5.20 (s, 2H); 4.58 (s, 2H); 4.47 (d,J=6.7 Hz, 2H); 3.79 (s, 3H); 2.24 (s, 3H).

The above ester (0.61 g, 1.16 mmol) was dissolved in ethanol (50 mL), asolution of lithium hydroxide monohydrate (0.09 g, 2.14 mmol) in water(4 mL) was added and the mixture was left to stand for 72 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL) and neutralized with 2 M hydrochloric acid. The mixture wasextracted with chloroform (2×50 mL); the organic solution was dried withanhydrous potassium carbonate and subsequently evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,chloroform/ether 2:1) affording oil which was triturated with hexaneyielding the title compound as amorphous solid.

Yield: 0.40 g (67%).

R_(F) (SiO₂, chloroform/ethanol 90:10): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (s, 1H); 7.59 (s, 1H);7.47 (d, J=7.2 Hz, 2H); 7.25 (d, J=8.1 Hz, 2H); 7.15 (m, 4H); 6.66 (d,2H); 6.56 (d, 1H); 6.30 (m, 2H); 5.24 (s, 2H); 4.59 (s, 2H); 4.47 (d,J=6.6 Hz, 2H); 2.24 (s, 3H).

Example 17(E)-[2-Methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(morpholin-4-yl)propynyl]-phenyl]allyloxy]phenoxy]aceticAcid

In nitrogen atmosphere, 0.15 M solution of tri(tert-butyl)phosphine incyclohexane (6.60 mL, 0.990 mmol) andtris(dibenzylideneacetone)dipalladium chloroform complex (252 mg, 0.243mmol) were added to a degassed solution of 3-(4-bromophenyl)propargylalcohol (1.82 g, 8.62 mmol; example 2) andtributyl-(5-methylthiophen-2-yl)tin (4.18 g, 10.8 mmol; preparedaccording to J. Med. Chem. 2001, 44, 3355) in dry N,N-dimethylformamide(50 mL). The reaction mixture was stirred at 50° C. for 2 h, cooled downand 10% aqueous solution of potassium fluoride (5 mL) was added. Theformed suspension was stirred for 15 min, filtered through a paddle ofsilica gel and the solid mass was thoroughly washed with ethyl acetate(180 mL). The combined filtrates were washed with brine (3×50 mL), 10%aqueous solution of potassium fluoride (2×50 mL), water (50 mL) andbrine (2×50 mL). The organic solution was dried with anhydrous magnesiumsulfate and its evaporation gave oil that was purified by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1) yielding3-[4-(5-methylthiophen-2-yl)phenyl]propargyl alcohol as brownish solidmass.

Yield: 1.16 g (59%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.49 (dm, J=8.5 Hz, 2H); 7.41(dm, J=8.6 Hz, 2H); 7.14 (d, J=3.6 Hz, 1H); 6.73 (dd, J=3.6 and 1.0 Hz,1H); 4.51 (d, J=5.9 Hz, 2H); 2.51 (d, J=0.9 Hz, 1H); 1.67 (bt, J=5.6 Hz,1H).

Sodium methoxide (16 mg, 0.296 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (5.1 mL, 5.1 mmol) undernitrogen. The mixture was cooled to 0° C. and a solution of the abovehydroxy derivative (1.16 g, 5.08 mmol) in tetrahydrofuran (5 mL) wasadded over 30 min. The reaction was stirred at 0° C. for 3.5 h; dryethyl acetate (1.50 mL, 15.4 mmol) was added and the whole mixture wasstirred at ambient temperature for 60 min. A degassed solution of1,4-diiodobenzene (1.77 g, 5.37 mmol) in dry tetrahydrofuran (5 mL),anhydrous zinc chloride (0.42 g, 3.08 mmol),tris(dibenzylidene-acetone)dipalladium chloroform complex (0.11 g, 0.11mmol), and tri-2-furylphosphine (0.13 g, 0.56 mmol) were added; themixture was degassed and was then heated at 65° C. for 19 h undernitrogen. The suspension was cooled down; methanol (2.5 mL) was addedand the mixture was stirred for additional 1 h. The reaction mixture wasdiluted with ether (25 mL) and saturated aqueous solution of ammoniumchloride (1.5 mL) was added. The mixture was filtered through a paddleof silica gel and the paddle was thoroughly washed with ether (40 mL).Solvents were evaporated in vacuo and the residue was separated by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1)affording (Z)-3-(4-iodophenyl)-3-[4-(5-methylthiophen-2-yl)phenyl]allylalcohol as solidifying oil.

Yield: 0.65 g (30%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.43 (dm, J=8.2 Hz, 2H); 7.48(dm, J=8.3 Hz, 2H); 7.23 (dm, J=8.3 Hz, 2H); 7.13 (d, J=3.6 Hz, 1H);6.96 (dm, J=8.2 Hz, 2H); 6.74 (dd, J=3.6 and 0.8 Hz, 1H); 6.26 (t, J=6.8Hz, 1H); 4.23 (dd, J=6.8 and 5.6 Hz, 2H); 2.52 (d, J=0.9 Hz, 1H); 1.43(t, J=5.6 Hz, 1H).

The above allyl alcohol (0.65 g, 1.50 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.33 g, 1.68 mmol; example 2) andtriphenylphosphine (0.48 g, 1.83 mmol) were dissolved in a mixture ofanhydrous toluene (30 mL) and tetrahydrofuran (10 mL). The mixture wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.35 mL, 1.77 mmol) in anhydroustetrahydrofuran (5 mL) was added dropwise during 10 min. The reactionmixture was allowed to warm up the ambient temperature with the bath andthen was stirred overnight. The solvents were evaporated in vacuo andthe residue was submitted to flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 6:1) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-[4-(5-methylthiophen-2-yl)phenyl]allyloxy]-2-methyl-phenoxy]acetateas solid mass.

Yield: 484 mg (53%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.50 (dm, J=8.4 Hz, 2H); 7.48(dm, J=8.5 Hz, 2H); 7.23 (dm, J=8.5 Hz, 2H); 7.13 (d, J=3.5 Hz, 1H);6.99 (dm, J=8.3 Hz, 2H); 6.75 (dd, J=3.5 and 1.1 Hz, 1H); 6.71 (d, J=2.8Hz, 1H); 6.65 (d, J=8.8 Hz, 1H); 6.61 (dd, J=9.0 and 2.9 Hz, 1H); 6.35(t, J=6.7 Hz, 1H); 4.61 (s, 2H); 4.51 (d, J=6.8 Hz, 2H); 3.81 (s, 3H);2.52 (bs, 3H); 2.28 (s, 3H).

4-Propargylmorpholine (80 mg, 0.639 mmol) and diisopropylamine (0.30 mL,2.14 mmol) were added to a solution of the above iodo derivative (245mg, 0.401 mmol) in tetrahydrofuran (5 mL). The mixture was degassed andcopper(I) iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladiumdichloride (15 mg, 0.021 mmol) were added. The reaction mixture wasstirred at ambient temperature for 2 h, filtered and the filtrate wasevaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 1:1 with 0.1%of triethylamine) yielding methyl(E)-[2-methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]acetateas solidifying oil.

Yield: 208 mg (85%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.05.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.49 (dm, J=8.3 Hz, 2H); 7.48(dm, J=8.5 Hz, 2H); 7.24 (dm, J=8.3 Hz, 2H); 7.19 (d, J=8.3 Hz, 2H);7.13 (d, J=3.6 Hz, 1H); 6.74 (dd, J=3.5 and 1.0 Hz, 1H); 6.70 (d, J=2.7Hz, 1H); 6.65 (d, J=8.9 Hz, 1H); 6.59 (dd, J=8.9 and 2.7 Hz, 1H); 6.35(t, J=6.7 Hz, 1H); 4.60 (s, 2H); 4.52 (d, J=6.7 Hz, 2H); 3.81 (m, 7H);3.56 (s, 2H); 2.68 (m, 4H); 2.52 (bs, 3H); 2.27 (s, 3H).

To a solution of the above ester (208 mg, 0.342 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (28.5 mg, 0.679 mmol) in distilled water (1 mL)was added under cooling to 0° C. The solution was stirred for 3 h undercooling, acetic acid (0.039 mL; 0.682 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withdichloromethane (50 mL) and the resulting heterogeneous mixture waswashed with water (2×15 mL) and brine (2×15 mL). The organic solutionwas dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (3×5 mL) yielding the title acid astan solid.

Yield: 112 mg (55%).

M.p.: 151-187° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.47 (dm, J=8.4 Hz, 2H); 7.43(dm, J=8.1 Hz, 2H); 7.22 (dm, J=8.4 Hz, 2H); 7.13 (m, 3H); 6.73 (dd,J=3.5 and 1.0 Hz, 1H); 6.69 (d, J=2.9 Hz, 1H); 6.61 (d, J=9.0 Hz, 1H);6.46 (dd, J=8.8 and 3.0 Hz, 1H); 6.37 (t, J=6.8 Hz, 1H); 4.57 (s, 2H);4.57 (d, J=6.9 Hz, 2H); 3.85 (m, 4H); 3.70 (s, 2H); 2.90 (m, 4H); 2.52(bs, 3H); 2.26 (s, 3H).

Example 18(Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]phenoxy]aceticAcid

A solution of methyl(Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)]allyloxy]-phenoxy]acetate(310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL)and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg,1.17 mmol) was added in argon atmosphere. The solution was cooled down;tetrakis(triphenylphosphine)-palladium (55 mg, 0.047 mmol) and copper(I)iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture wasstirred at ambient temperature for 48 h, then evaporated in vacuo andthe residue was dissolved in ethyl acetate (20 mL). The solution waswashed with water (3×15 mL), dried with anhydrous magnesium sulphate andevaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yieldingmethyl(Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.

Yield: 232 mg (79%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.50-7.72 (m, 4H); 7.10-7.28(m, 8H); 6.69 (m, 1H); 6.46 (m, 2H); 6.28 (t, J=6.8 Hz, 1H); 4.58 (s,2H); 4.51 (d, J=6.8 Hz, 2H); 3.79 (s, 3H); 2.34 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (232 mg, 0.461 mmol) intetrahydrofuran/methanol mixture (3:5, 11 mL), a solution of lithiumhydroxide monohydrate (38.6 mg, 0.921 mmol) in distilled water (1 mL)was added under cooling to 0° C. The solution was stirred at ambienttemperature for 4 h, then neutralized with acetic acid (38.6 mg, 0.921mmol) and extracted with ether (2×30 mL). The extracts were washed withwater (2×10 mL) and brine (10 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanesyielding the title acid as tan solid.

Yield: 144 mg (64%).

M.p.: 121-130° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.68 (d, J=5.0 Hz, 1H); 7.75(m, 1H); 7.55 (m, 3H); 7.31 (m, 1H); 7.17-7.08 (m, 6H); 6.68 (m, 2H);6.50 (dd, J=8.6 and 2.9 Hz, 1H); 6.30 (t, J=6.8 Hz, 1H); 4.20 (s, 2H);4.47 (d, J=6.8 Hz, 2H); 2.34 (s, 3H); 2.25 (s, 3H).

Example 19(Z)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]-aceticAcid

A solution of methyl(Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)]allyloxy]-phenoxy]acetate(310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL)and triethylamine (9 mL) was degassed and 1-propargyl-1H-pyrazole (124mg, 1.17 mmol) was added in argon atmosphere. The solution was cooleddown; tetrakis(triphenylphosphine)palladium (54 mg, 0.046 mmol) andcopper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixturewas stirred at ambient temperature for 4 days, subsequently evaporatedin vacuo and the residue was dissolved in ethyl acetate (20 mL). Thesolution was washed with water (3×15 mL), dried with anhydrous magnesiumsulphate and evaporated in vacuo. The residue was purified by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3)yielding methyl(Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(3-pyrazol-1-ylpropynyl)phenyl]allyloxy]phenoxy]acetate.

Yield: 214 mg (72%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (s, 1H); 7.56 (s, 1H);7.47 (d, J=8.3 Hz, 2H); 7.08-7.18 (m, 6H); 6.54-6.68 (m, 3H); 6.32 (m,1H); 6.28 (t, J=6.7 Hz, 1H); 5.20 (s, 2H); 4.58 (s, 2H); 4.47 (d, J=6.7Hz, 2H); 3.79 (s, 3H); 2.34 (s, 3H); 2.24 (s, 3H).

To a solution of the above ester (214 mg, 0.422 mmol) intetrahydrofuran/methanol mixture (3:5, 11 mL), a solution of lithiumhydroxide monohydrate (35.4 mg, 0.845 mmol) in distilled water (1 mL)was added under cooling to 0° C. The solution was stirred at ambienttemperature for 4 h, then neutralized with acetic acid (48.3 mg, 0.845mmol) and extracted with ether (2×20 mL). The extracts were washed withwater (2×10 mL) and brine (10 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanesyielding the title acid as tan solid.

Yield: 129 mg (62%).

M.p.: 110-125° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69-7.08 (m, 10H); 6.65 (m,2H); 6.55 (m, 1H); 6.32 (s, 1H); 6.28 (t, J=6.3 Hz, 1H); 5.22 (s, 2H);4.60 (s, 2H); 4.46 (d, J=6.7 Hz, 2H); 2.33 (s, 3H); 2.24 (s, 3H).

Example 20(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]aceticAcid

4-Propargylmorpholine (193 mg, 1.55 mmol) and diisopropylamine (0.51 mL,3.64 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate(450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixturewas degassed and copper(I) iodide (12 mg, 0.063 mmol) andbis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 19 hand evaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, dichloromethane/methanol 99:1)yielding methyl(E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetateas brown oil.

Yield: 447 mg (99%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.70.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (d, J=8.3 Hz, 2H); 7.48(d, J=8.2 Hz, 2H); 7.35 (d, J=8.2 Hz, 2H); 7.14 (d, J=8.2 Hz, 2H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.8 Hz,1H); 6.37 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.53 (d, J=6.6 Hz, 2H); 3.79(m, 7H); 3.54 (s, 2H); 2.66 (m, 4H); 2.25 (s, 3H).

To a solution of the above ester (435 mg, 0.751 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (47 mg, 1.12 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2.5 h undercooling, glacial acetic acid (0.064 mL, 1.12 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with ether (3×20 mL). The combined organiclayers were washed with water (2×20 mL) and brine (2×20 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with hexanes (2×4 mL) yielding the title acid as whitecrystals.

Yield: 306 mg (72%).

M.p.: 150-157° C.

R_(F) (SiO₂, dichloromethane/methanol 90:10): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.54 (d, J=8.3 Hz, 2H); 7.43(d, J=8.2 Hz, 2H); 7.34 (d, J=8.1 Hz, 2H); 7.09 (d, J=8.2 Hz, 2H);6.67-6.58 (m, 2H); 6.47-6.43 (m, 1H); 6.38 (t, J=6.8 Hz, 1H); 4.55 (s,2H); 4.48 (d, J=6.7 Hz, 2H); 3.83 (m, 4H); 3.69 (s, 2H); 2.88 (m, 4H);2.24 (s, 3H).

Example 21(E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]aceticAcid

1-Propargylpiperidin-4-ol (215 mg, 1.55 mmol) and diisopropylamine (0.51mL, 3.64 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate(450 mg, 0.773 mmol; example 4) in tetrahydrofuran (10 mL). The mixturewas degassed and copper(I) iodide (12 mg, 0.063 mmol) andbis(triphenylphosphine)palladium(II) dichloride (27 mg, 0.039 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 20 hand evaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, dichloromethane/methanol98:2-97:3-95:5) yielding methyl(E)-[4-[3-[4-[3-(4-hydroxy-piperidin-1-yl)propynyl]-phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 402 mg (88%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (d, J=8.3 Hz, 2H); 7.48(d, J=8.2 Hz, 2H); 7.35 (d, J=8.2 Hz, 2H); 7.14 (d, J=8.2 Hz, 2H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.9 Hz,1H); 6.36 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.52 (d, J=6.6 Hz, 2H); 3.79(s, 3H); 3.74 (m, 1H); 3.54 (s, 2H); 2.90 (m, 2H); 2.45 (m, 2H); 2.25(s, 3H); 1.96 (m, 2H); 1.69 (m, ˜2H).

To a solution of the above ester (392 mg, 0.660 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (42 mg, 1.0 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2 h undercooling, glacial acetic acid (0.057 mL, 0.997 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with ether (7×20 mL). The combined organiclayers were washed with brine (2×30 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanes(2×4 mL) yielding the title acid as white crystals.

Yield: 62 mg (16%).

M.p.: 110-121° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.54 (d, J=8.4 Hz, 2H); 7.42(d, J=8.2 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.07 (d, J=8.2 Hz, 2H);6.66-6.55 (m, 2H); 6.41 (t, J=6.8 Hz, 1H); 6.33 (m, 1H); 4.50 (s, 2H);4.44 (d, J=6.8 Hz, 2H); 3.93 (m, 1H); 3.82 (s, 2H); 3.24 (m, 2H); 2.94(m, ˜2H); 2.24 (s, 3H); 2.03 (m, 2H); 1.83 (m, 2H).

Example 22(E)-[2-Methyl-4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]aceticAcid

N,N-Dimethylpropargylamine (0.11 mL, 1.03 mmol) and diisopropylamine(0.34 mL, 2.42 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate(300 mg, 0.515 mmol; example 4) in tetrahydrofuran (10 mL). The mixturewas degassed and copper(I) iodide (8 mg, 0.042 mmol) andbis(triphenylphosphine)palladium(II) dichloride (18 mg, 0.026 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 20 hand evaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, dichloromethane/methanol 98:2)yielding methyl(E)-[2-methyl-4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetateas brown oil.

Yield: 279 mg (99%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (d, J=8.3 Hz, 2H); 7.48(d, J=8.0 Hz, 2H); 7.36 (d, J=8.2 Hz, 2H); 7.14 (d, J=8.0 Hz, 2H); 6.68(d, J=2.6 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.9 and 2.7 Hz,1H); 6.36 (t, J=6.5 Hz, 1H); 4.59 (s, 2H); 4.53 (d, J=6.5 Hz, 2H); 3.79(s, 3H); 3.50 (s, 2H); 2.39 (s, 6H); 2.25 (s, 3H).

To a solution of the above ester (266 mg, 0.495 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (62 mg, 1.48 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 3 h undercooling, glacial acetic acid (0.086 mL, 1.50 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (30 mL) and water (20 mL); the phases were separated and theaqueous phase was extracted with ether (3×10 mL). The combined organiclayers were washed with water (2×10 mL) and brine (2×10 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with hexanes (2×4 mL) yielding the title acid as yellowcrystals.

Yield: 83 mg (32%).

M.p.: 49-64° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (d, J=8.3 Hz, 2H); 7.44(d, J=8.0 Hz, 2H); 7.36 (d, J=8.2 Hz, 2H); 7.13 (d, J=8.0 Hz, 2H); 6.68(s, 1H); 6.60 (d, J=9.1 Hz, 1H); 6.42 (t, 1H); 6.40 (m, 1H); 4.51 (s,2H); 4.43 (d, J=6.7 Hz, 2H); 3.87 (s, 2H); 2.66 (s, ˜6H); 2.25 (s, 3H).

Example 23(E)-[2-Methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]aceticAcid

2-Ethynyl-5-methylthiophene (161 mg, 1.32 mmol) and diisopropylamine(0.43 mL, 3.10 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate(384 mg, 0.659 mmol; example 4) in tetrahydrofuran (10 mL). The mixturewas degassed and copper(I) iodide (10 mg, 0.053 mmol) andbis(triphenylphosphine)palladium(II) dichloride (23 mg, 0.033 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 19 hand subsequently evaporated in vacuo. The residue was purified by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate15:1-12:1) yielding methyl(E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetateas brown oil.

Yield: 326 mg (86%).

R_(F) (SiO₂, hexanes/ethyl acetate 9:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.56 (d, J=8.0 Hz, 2H); 7.54(d, J=8.0 Hz, 2H); 7.37 (d, J=8.2 Hz, 2H); 7.17 (d, J=8.2 Hz, 2H); 7.11(d, J=3.6 Hz, 1H); 6.68 (s, 2H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.9and 2.8 Hz, 1H); 6.37 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.55 (d, J=6.6Hz, 2H); 3.79 (s, 3H); 2.50 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (319 mg, 0.553 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (70 mg, 1.67 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2.5 h undercooling, glacial acetic acid (0.095 mL, 1.66 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (30 mL) and water (20 mL); the phases were separated and theaqueous phase was extracted with ether (3×10 mL). The combined organiclayers were washed with water (2×10 mL) and brine (2×10 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with hexanes (2×4 mL) yielding the title acid as browncrystals.

Yield: 233 mg (75%).

M.p.: 127-134° C.

R_(F) (SiO₂, dichloromethane/methanol 90:10): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.56 (d, J=8.0 Hz, 2H); 7.54(d, J=8.1 Hz, 2H); 7.36 (d, J=8.2 Hz, 2H); 7.17 (d, J=8.2 Hz, 2H); 7.11(d, J=3.5 Hz, 1H); 6.69-6.65 (m, 3H); 6.59 (dd, J=8.8 and 2.7 Hz, 1H);6.37 (t, J=6.6 Hz, 1H); 4.61 (s, 2H); 4.55 (d, J=6.6 Hz, 2H); 2.50 (s,3H); 2.25 (s, 3H).

Example 24(E)-[2-Methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-allyloxy]phenoxy]aceticAcid

1-Propargylpyrrolidine (168 mg, 1.54 mmol) and diisopropylamine (0.27mL, 1.93 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-[4-(5-methylthiophen-2-yl)phenyl]allyloxy]-2-methylphenoxy]acetate(235 mg, 0.385 mmol; prepared as described in example 17) intetrahydrofuran (5 mL). The mixture was degassed and copper(I) iodide(15 mg, 0.079 mmol) and bis(triphenylphosphine)-palladium(II) dichloride(27 mg, 0.038 mmol) were added. The reaction mixture was stirred atambient temperature for 2.5 h and subsequently evaporated in vacuo. Theresidue was purified by flash column chromatography (silica gel Fluka60, dichloromethane/methanol 98:2+0.5% of triethylamine) yielding methyl(E)-[2-methyl-4-[3-[4-(5-methylthiophen-2-yl)phenyl]-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-allyloxy]phenoxy]acetateas brownish oil.

Yield: 186 mg (82%).

R_(F) (SiO₂, dichloromethane/methanol 98:2): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (m, 4H); 7.21 (dm, J=8.6Hz, 2H); 7.16 (dm, J=8.3 Hz, 2H); 7.11 (d, J=3.5 Hz, 1H); 6.72 (dd,J=3.5 and 1.0 Hz, 1H); 6.68 (d, J=2.9 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H);6.57 (dd, J=9.0 and 2.9 Hz, 1H); 6.32 (t, J=6.7 Hz, 1H); 4.58 (s, 2H);4.50 (d, J=6.7 Hz, 2H); 3.76 (s, 3H); 3.67 (s, 2H); 2.73 (m, 4H); 2.50(d, J=0.8 Hz, 3H); 2.25 (s, 3H); 1.86 (m, 4H).

To a solution of the above ester (186 mg, 0.314 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (29 mg, 0.691 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 45 min undercooling, acetic acid (0.040 mL; 0.699 mmol) was added and the resultingmixture was stirred for further 15 min. The solution was diluted withdichloromethane (50 mL) and the resulting heterogeneous mixture waswashed with water (3×15 mL) and brine (2×15 mL).

The organic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was triturated withhexanes/dichloromethane (1:5, 6 mL) and subsequently with pure hexanes(2×5 mL) yielding the title acid as tan solid.

Yield: 100 mg (55%).

M.p.: 172-177° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃+CD₃COOD, δ_(H)): 7.47 (dm, J=8.3 Hz,2H); 7.45 (dm, J=8.6 Hz, 2H); 7.19 (dm, J=8.1 Hz, 4H); 7.09 (d, J=3.6Hz, 1H); 6.70 (dd, J=3.6 and 1.0 Hz, 1H); 6.67 (d, J=2.8 Hz, 1H); 6.62(d, J=9.0 Hz, 1H); 6.54 (dd, J=9.0 and 2.9 Hz, 1H); 6.35 (t, J=6.8 Hz,1H); 4.59 (s, 2H); 4.47 (d, J=6.8 Hz, 2H); 4.26 (s, 2H); 3.51 (m, 4H);2.48 (d, J=0.8 Hz, 3H); 2.22 (s, 3H) 2.10 (m, overlap).

Example 25(E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(pyrrolidin-1-yl)propynyl)phenyl]-allyloxy]phenoxy]aceticAcid

A solution of 5-iodo-2-methylbenzo[b]furan (12.1 g, 46.9 mmol) in drytetrahydrofuran (50 mL) was degassed and copper(I)iodide (280 mg, 1.5mmol), tetrakis(triphenylphosphine)palladium (1.7 g, 1.5 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (9.1 g, 60.0 mmol) were added. Thereaction solution was degassed again and propargyl alcohol (3.4 g, 60.7mmol) was added under inert atmosphere at ambient temperature. Thereaction mixture was stirred (initially under cooling with ice water)for 48 h, then treated with water (20 mL) and acidified with 2 Mhydrochloric acid (20 mL). The organic phase was separated and theaqueous phase was extracted with ether (4×30 mL). The combined organicphases were dried with anhydrous magnesium sulfate and concentrated invacuo yielding brown solid. The residue was purified by columnchromatography (silica gel Fluka 60, benzene) yielding3-(2-methylbenzo[b]furan-5-yl)prop-2-yn-1-ol.

Yield: 6.4 g (73%).

M.p.: 101.5-102.5° C. (hexane).

R_(F) (SiO₂, chloroform): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (s, 1H); 7.29 (m, 2H);6.32 (s, 1H); 4.51 (s, 2H); 2.43 (s, 3H); 2.05 (bs, 1H).

Sodium methoxide (0.05 g, 0.9 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (20 mL, 20 mmol). The mixture wascooled to 0° C., and a solution of the above alcohol (3.67 g, 19.7 mmol)in tetrahydrofuran (30 mL) was slowly added. The reaction mixture wasstirred at 0° C. for 1.5 h and subsequently for 1.5 h at ambienttemperature. Ethyl acetate (3.3 mL, 34 mmol) was added at 0° C. and themixture was then stirred for 20 min without cooling. 1,4-Diiodobenzene(6.6 g, 20 mmol), anhydrous zinc chloride (1.64 g, 12 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (0.41 g, 0.4mmol), and tri-(2-furyl)phosphine (0.37 g, 1.6 mmol) were added; themixture was evacuated and kept under nitrogen. Reaction mixture washeated at 65° C. for 16 h, and then cooled down. Methanol (10 mL) wasadded and the mixture was stirred for additional 1 h. The reactionsuspension was diluted with ether (150 mL), and saturated aqueoussolution of ammonium chloride (5 mL) was added. The mixture was filteredthrough a paddle of silica gel and the solid phase was thoroughly washedwith ether. Solvents were evaporated in vacuo and the residue wassubmitted to column chromatography (silica gel Fluka 60;benzene/chloroform 1:0-0:1) affording(Z)-3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyl alcohol aslight brown solid.

Yield: 2.4 g (31%).

M.p.: 103-113° C.

R_(F) (SiO₂, chloroform/ether 2:1): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.66 (d, J=7.9 Hz, 2H); 7.27(m, 2H); 7.07 (d, J=8.5, 1H); 6.89 (d, J=7.9 Hz, 2H); 6.27 (s, 1H); 6.18(t, J=6.9 Hz, 1H); 4.17 (d, J=6.9 Hz, 2H); 2.41 (s, 3H); 2.08 (bs, 1H).

The above allyl alcohol (2.20 g, 5.64 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.20 g, 6.1 mmol; prepared as inexample 2) and triphenylphosphine (1.70 g, 6.48 mmol) were dissolved ina mixture of anhydrous toluene (20 mL) and tetrahydrofuran (10 mL). Themixture was cooled to 0° C., kept under nitrogen and diisopropylazodicarboxylate (1.50 g, 7.0 mmol) was added dropwise. The reactionmixture was stirred at 0° C. for 3 h and then at ambient temperature for72 h. The solvents were evaporated in vacuo and the residue wassubmitted to column chromatography (silica gel Fluka 60, benzene)affording methyl(Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetateas solid mass.

Yield: 1.64 g (50%).

M.p.: 121-128° C.

R_(F) (SiO₂, chloroform): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.2 Hz, 2H); 7.28(m, 2H); 7.10 (dd, J=8.6 and 1.2 Hz, 2H); 6.97 (d, J=8.2 Hz, 2H); 6.69(d, J=2.3 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.58 (dd, J=8.7 and 2.3 Hz);6.30 (s, 1H); 6.27 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.49 (d, J=6.7 Hz,2H); 3.79 (s, 3H); 2.44 (s, 3H); 2.25 (s, 3H).

N-Propargylpyrrolidine (250 mg, 2.29 mmol) was added under nitrogenatmosphere to a degassed solution of the above ester (400 mg, 0.68 mmol)in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL) Thesolution was cooled, tetrakis(triphenylphosphine)palladium (71 mg, 0.061mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reactionmixture was stirred at ambient temperature for 96 h, diluted withbenzene (100 mL), decanted and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, benzene/ethylacetate 1:0-0:1) yielding methyl(E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]allyloxy]phenoxy]acetate.

Yield: 180 mg (48%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.3 Hz, 2H); 7.29(m, 2H); 7.16 (d, J=8.3 Hz, 2H); 7.11 (dd, J=8.6 and 1.8 Hz, 1H); 6.68(d, J=2.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.58 (dd, J=8.7 and 2.7 Hz),1H); 6.29 (s, 1H); 6.26 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7Hz, 2H); 3.79 (s, 3H); 3.66 (s, 2H); 2.71 (m, 4H); 2.44 (s, 3H); 2.25(s, 3H); 1.85 (m, 4H).

The above ester (0.16 g, 0.29 mmol) was dissolved in ethanol (20 mL), asolution of lithium hydroxide monohydrate (0.05 g, 1.19 mmol) in water(2 mL) was added and the mixture was left to stand for 48 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.2 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo affording oilwhich was triturated with hexanes yielding the title compound asamorphous solid.

Yield: 0.12 g (77%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.43 (d, J=8.1 Hz, 2H); 7.28(m, 2H); 7.18 (d, J=8.1 Hz, 2H); 7.09 (dd, J=8.6 and 1.4 Hz, 1H); 6.65(m, 2H); 6.49 (dd, J=8.7 and 2.6 Hz, 1H); 6.30 (t, J=6.9 Hz, 1H); 6.28(s, 1H); 4.48 (s, 2H); 4.44 (d, J=6.9 Hz, 2H); 4.09 (s, 2H); 3.31 (bs,4H); 2.43 (s, 3H); 2.25 (s, 3H); 2.02 (bs, 4H).

Example 26(E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(morpholin-4-yl)propynyl)phenyl]-allyloxy]phenoxy]aceticAcid

N-Propargylmorpholine (270 mg, 2.16 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.68 mmol; prepared as described in example 25) in a mixture oftetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooledto 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) andcopper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture wasstirred at ambient temperature for 96 h, diluted with benzene (100 mL),decanted and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1)yielding methyl(E)[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]phenoxy]acetate.

Yield: 340 mg (88%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.70.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.3 Hz, 2H); 7.29(m, 2H); 7.17 (d, J=8.3 Hz, 2H); 7.11 (dd, J=8.6 and 1.8 Hz, 1H); 6.68(d, J=2.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.58 (dd, J=8.7 and 2.7 Hz);6.29 (s, 1H); 6.26 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz,2H); 3.79 (s, 3H); 3.78 (m, 4H); 3.53 (s, 2H); 2.66 (m, 4H); 2.43 (s,3H); 2.25 (s, 3H).

The above ester (0.34 g, 0.60 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.08 g, 1.9 mmol) in water (3mL) was added and the mixture was left to stand for 48 h. The solventswere evaporated in vacuo; the residue was diluted with water (25 mL) andacidified with acetic acid (0.3 mL). The formed precipitate was filteredoff and dried in the air yielding the title compound as amorphous solid.

Yield: 0.32 g (96%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.2 Hz, 2H); 7.27(m, 2H); 7.14 (d, J=8.2 Hz, 2H); 7.09 (dd, J=8.7 and 1.7 Hz, 1H); 6.68(d, J=2.7 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.49 (dd, J=8.8 and 2.7 Hz,1H); 6.28 (s and t, 2H); 4.53 (s, 2H); 4.46 (d, J=6.8 Hz, 2H); 3.83 (bs,4H); 3.71 (s, 2H); 2.90 (bs, 4H); 2.43 (s, 3H); 2.24 (s, 3H).

Example 27(E)-[2-Methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-(3-(dimethylamino)propynyl)phenyl]-allyloxy]phenoxy]aceticAcid

Under nitrogen atmosphere, 3-(N,N-dimethylamino)propyne (250 mg, 3.00mmol) was added to a degassed solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate(370 mg, 0.63 mmol; prepared as described in example 25) in a mixture oftetrahydrofuran (6 mL) and triethylamine (6 mL) The solution was cooledto 0° C., tetrakis(triphenylphosphine)palladium (71 mg, 0.06 mmol) andcopper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture wasstirred at ambient temperature for 72 h, diluted with benzene (100 mL),decanted and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1)yielding methyl(E)-[2-methyl-4-[3-(2-methylbenzo[b]furan-5-yl)-3-[4-[3-(dimethylamino)propynyl]phenyl]-allyloxy]phenoxy]acetate.

Yield: 260 mg (78%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.3 Hz, 2H); 7.29(m, 2H); 7.17 (d, J=8.3 Hz, 2H); 7.11 (dd, J=8.6 and 1.8 Hz, 1H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.58 (dd, J=8.7 and 2.7 Hz);6.29 (s, 1H); 6.26 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz,2H); 3.79 (s, 3H); 3.50 (s, 2H); 2.44 (s, 3H); 2.39 (s, 6H); 2.25 (s,3H).

The above ester (0.26 g, 0.50 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.08 g, 1.9 mmol) in water (3mL) was added and the mixture was left to stand for 48 h. The solventswere evaporated in vacuo; the residue was diluted with water (25 mL),acidified with acetic acid (0.25 mL) and extracted with chloroform (2×50mL). The organic solution was dried with anhydrous potassium carbonateand subsequently evaporated in vacuo affording oil which was trituratedwith hexanes yielding the title compound as amorphous solid.

Yield: 0.24 g (95%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.29(m, 2H); 7.19 (d, J=8.1 Hz, 2H); 7.09 (dd, J=8.5 and 1.5 Hz, 1H); 6.65(m, 2H); 6.53 (dd, J=8.6 and 2.5 Hz, 1H); 6.29 (s and t, 2H); 4.49 (s,2H); 4.45 (d, J=6.9 Hz, 2H); 3.90 (s, 2H); 2.67 (s, 6H); 2.42 (s, 3H);2.26 (s, 3H).

Example 28(E)-[4-[3-[4-[3-[N-(2-Hydroxyethyl)-N-methylamino]propynyl]phenyl]-3-(2-methylbenzo[b]-furan-5-yl)allyloxy]-2-methylphenoxy]aceticAcid

2-(N-Methyl-N-propargylamino)ethanol (440 mg, 3.89 mmol) was added undernitrogen atmosphere to a degassed solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.68 mmol; prepared as described in example 25) in a mixture oftetrahydrofuran (6 mL) and triethylamine (6 mL). The solution was cooledto 0° C. and tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol)and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixturewas stirred at ambient temperature for 72 h, diluted with benzene (100mL), decanted and evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, benzene/ethyl acetate1:0-0:1) yielding methyl(E)-[4-[3-[4-[3-[N-(2-hydroxyethyl)-N-methylamino]-propynyl]phenyl]-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate.

Yield: 340 mg (89%).

R_(F) (SiO₂, chloroform/ethanol 1:1): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.23(m, 2H); 7.17 (d, J=8.1 Hz, 2H); 7.11 (dd, J=8.6 and 1.8 Hz, 1H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.58 (dd, J=8.7 and 2.7 Hz);6.29 (s, 1H); 6.27 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz,2H); 3.79 (s, 3H); 3.66 (t, J=5.2 Hz, 2H); 3.62 (s, 2H); 2.72 (t, J=5.2Hz, 2H); 2.43 (s, 3H); 2.25 (s, 3H).

The above ester (0.34 g, 0.61 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.08 g, 1.90 mmol) in water(3 mL) was added and the mixture was left to stand for 48 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo affording oilwhich was triturated with hexanes yielding the title compound asamorphous solid.

Yield: 0.29 g (88%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.05.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.43 (d, J=8.1 Hz, 2H); 7.29(m, 2H); 7.17 (d, J=8.1 Hz, 2H); 7.09 (dd, J=8.7 and 1.5 Hz, 1H); 6.67(d, J=2.7 Hz, 1H); 6.63 (d, J=8.7 Hz, 1H); 6.49 (dd, J=8.7 and 2.7 Hz,1H); 6.29 (s and t, 2H); 4.49 (s, 2H); 4.43 (d, J=6.9 Hz, 2H); 3.97 (s,2H); 3.85 (bs, 2H); 3.08 (bs, 2H); 2.72 (s, 3H); 2.43 (s, 3H); 2.24 (s,3H).

Example 29(E)-[2-Methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]aceticAcid

N-Propargylpyrrolidine (113 mg, 1.04 mmol) and diisopropylamine (0.339mL, 2.42 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate(300 mg, 0.515 mmol; prepared as described in example 4) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II) dichloride(18 mg, 0.026 mmol) were added. The reaction mixture was stirred atambient temperature for 21 h. Further portions of N-propargylpyrrolidine(113 mg, 1.04 mmol), diisopropylamine (0.339 mL, 2.42 mmol), copper(I)iodide (8 mg, 0.042 mmol) and bis(triphenylphosphine)palladium(II)dichloride (18 mg, 0.026 mmol) were added and reaction mixture wasstirred at 50° C. for further 5 h and then evaporated in vacuo. Theresidue was purified by flash column chromatography (silica gel Fluka60, dichloromethane/methanol 99:1-98:2) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(pyrrolidin-1-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetateas brown oil.

Yield: 249 mg (86%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55 (d, J=8.2 Hz, 2H); 7.49(d, J=8.3 Hz, 2H); 7.35 (d, J=8.2 Hz, 2H); 7.15 (d, J=8.3 Hz, 2H); 6.68(d, J=2.8 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.9 and 2.9 Hz,1H); 6.37 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.52 (d, J=6.6 Hz, 2H); 3.79(s, 3H); 3.78 (s, 2H); 2.89 (m, 4H); 2.25 (s, 3H); 1.93 (m, 4H).

To a solution of the above ester (242 mg, 0.429 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (54 mg, 1.29 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2 h undercooling, glacial acetic acid (0.074 mL, 1.29 mmol) was added and themixture was stirred for further 10 min. The solution was diluted withether (30 mL) and water (20 mL); the phases were separated and theaqueous phase was extracted with ether (3×10 mL). The combined organiclayers were washed with water (2×10 mL) and brine (2×10 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative HPLC yielding the title acid as brown oil.

Yield: 58 mg (25%).

M.p.: --- (oil).

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.50 (d, J=7.0 Hz, ˜2H); 7.43(d, J=6.8 Hz, ˜2H); 7.29 (d, J=9.4 Hz, ˜2H); 7.10 (d, J=7.2 Hz, 2H);6.57 (m, 2H); 6.41 (m, ˜1H); 6.33 (m, ˜1H); 4.36 (m. 4H); 3.97 (s, 2H);3.14 (s, 4H); 2.14 (s, 3H); 1.96 (s, 4H).

Example 30(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

To a degassed solution of 1-bromo-4-tert-butylbenzene (5 g, 23.5 mmol)in tetrahydrofuran (25 mL) was added in the following order: copper(I)iodide (134 mg, 0.704 mmol), tetrakis(triphenylphosphine)palladium (813mg, 0.704 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.2 mL, 28.1mmol). The resulting mixture was degassed again and a solution ofpropargyl alcohol (1.64 mL, 28.2 mmol) in tetrahydrofuran (2 mL) wasadded over period of 10 min. The reaction mixture was slowly heated upto 50° C. and then stirred at this temperature over night. The mixturewas diluted with ether (50 mL), washed with water (20 mL), 15%hydrochloric acid (2×20 mL) and saturated aqueous solution of sodiumhydrogen carbonate (25 mL). The organic solution was dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, hexanes/ethylacetate 5:1) affording 3-(4-tert-butylphenyl)prop-2-yn-1-ol.

Yield: 4.3 g (97%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.38 (d, J=8.7 Hz, 2H); 7.33(d, J=8.7 Hz, 2H); 4.49 (d, J=5.7 Hz, 2H); 1.31 (s, 9H).

Sodium methoxide (62 mg, 1.15 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (22.8 mL, 22.8 mmol) under nitrogen.The mixture was cooled to 0° C. and a solution of the above hydroxyderivative (4.3 g, 22.8 mmol) in tetrahydrofuran (22 mL) was added over30 min. The reaction was stirred at 0° C. for 3 h; dry ethyl acetate(6.9 mL, 70.6 mmol) was added and the whole mixture was stirred atambient temperature for 10 min. A degassed solution of 1,4-diiodobenzene(7.9 g, 24.0 mmol) in dry tetrahydrofuran (28 mL), anhydrous zincchloride (1.9 g, 13.9 mmol), tris(dibenzylideneacetone)dipalladiumchloroform complex (0.43 g, 0.415 mmol), and tri-2-furylphosphine (0.583g, 2.51 mmol) were added; the mixture was degassed and then heated at50° C. for 19 h under nitrogen. The suspension was cooled down; methanol(11.5 mL) was added and the mixture was stirred for additional 1 h. Thereaction mixture was diluted with ether (110 mL) and saturated aqueoussolution of ammonium chloride (5.8 mL) was added. The mixture wasfiltered through a paddle of silica gel and the paddle was thoroughlywashed with ether (500 mL). Solvents were evaporated in vacuo and theresidue was separated by flash column chromatography (silica gel Fluka60, hexanes/ethyl acetate 6:1) affording(Z)-3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyl alcohol as an oil.

Yield: 2.5 g (28%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=8.3 Hz, 2H); 7.33(d, J=8.5 Hz, 2H); 7.19 (d, J=8.6 Hz, 2H); 6.95 (d, J=8.3 Hz, 2H); 6.26(t, J=6.9 Hz, 1H); 4.20 (d, ˜2H (overlapped)); 1.33 (s, 9H).

The above allyl alcohol (2.46 g, 6.27 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.35 g, 6.88 mmol; example 2) andtriphenylphosphine (1.97 g, 7.51 mmol) were dissolved in a mixture ofanhydrous toluene (135 mL) and tetrahydrofuran (45 mL). The mixture wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (1.5 mL, 7.57 mmol) in anhydroustetrahydrofuran (15 mL) was added dropwise during 30 min. The reactionmixture was allowed to warm up the ambient temperature with the bath andthen stirred over night. The solvents were evaporated in vacuo and theresidue was submitted to flash column chromatography (silica gel Fluka60, hexanes/ethyl acetate 12:1-10:1) affording methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 2.38 g (67%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.3 Hz, 2H); 7.31(d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H); 6.96 (d, J=8.3 Hz, 2H); 6.68(d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.8 Hz,1H); 6.29 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 2.25 (s, 3H); 1.31 (s, ˜9H). 4-Propargylmorpholine (153 mg,1.22 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to asolution of the above iodo derivative (350 mg, 0.614 mmol) intetrahydrofuran (5 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium dichloride (22mg, 0.031 mmol) were added. The reaction mixture was stirred at ambienttemperature overnight, filtered and the filtrate was evaporated invacuo. The residue was purified by flash column chromatography (silicagel Fluka 60, dichloromethane/methanol 99:1) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas oil.

Yield: 334 mg (96%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.31(d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.2 Hz, 2H); 6.67(d, J=2.7 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.9 and 2.8 Hz,1H); 6.29 (t, J=6.6 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.78 (m, 4H); 3.54 (s, 2H); 2.66 (m, 4H); 2.24 (s, 3H); 1.31(s, 9H).

To a solution of the above ester (325 mg, 0.573 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (71 mg, 1.69 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 2.5 h undercooling, acetic acid (0.097 mL; 1.70 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withethyl acetate (40 mL) and water (30 mL); the phases were separated andthe aqueous phase was extracted with ethyl acetate (3×20 mL).

The combined organic layers were washed with water (2×20 mL) and brine(2×20 mL). The organic solution was dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanes(2×4 mL) yielding the title acid as yellow solid.

Yield: 227 mg (72%).

M.p.: 68-75° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.3 Hz, 2H); 7.30(d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H); 7.10 (d, J=8.1 Hz, 2H); 6.66(m, 1H); 6.58 (d, J=8.9 Hz, 1H); 6.43 (dd, J=8.5 and 2.3 Hz, 1H); 6.31(t, J=6.8 Hz, 1H); 4.53 (s, 2H); 4.44 (d, J=6.8 Hz, 2H); 3.82 (m, 4H);3.66 (s, 2H); 2.86 (m, ˜4H); 2.23 (s, 3H); 1.30 (s, 9H).

Example 31(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-(2-methyl-1,1-dioxobenzo[b]thiophen-5-ylethynyl)phenyl]-allyloxy]-2-methylphenoxy]aceticAcid

5-Bromo-2-methylbenzo[b]thiophene (8.0 g, 35.2 mmol; prepared accordingto J. Med. Chem. 1986, 29, 1643) was dissolved in acetic acid (200 mL);30% hydrogen peroxide (50 mL) was added and the mixture was refluxed for4 h. Water (500 mL) was added and the mixture was extracted with benzene(300 mL). The organic layer was evaporated in vacuo and the residue waspurified by column chromatography (silica gel Fluka 60, benzene)affording 5-bromo-2-methylbenzo[b]thiophene-1,1-dioxide.

Yield: 5.88 g (64%).

M.p.: 149-151° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.57 (s, 2H); 7.43 (s, 1H);6.74 (s, 1H); 2.23 (s, 3H).

A mixture of the above sulfone (5.88 g, 22.7 mmol),bis(triphenylphosphine)palladium(II) dichloride (0.175 g, 0.25 mmol),copper(II)acetate (50 mg, 0.275 mmol), ethynyltrimethylsilane (5.5 g,56.0 mmol) and triethylamine (60 mL) was refluxed under stirring for 6h. After cooling, the separated5-trimethylsilylethynyl-2-methylbenzo[b]thiophene-1,1-dioxide wascollected by filtration and washed with benzene.

Yield: 3.80 g (61%).

M.p.: 195-197° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.64 (d, J=7.8 Hz, 1H); 7.51(d, J=7.8 Hz, 1H); 7.35 (s, 1H); 6.74 (s, 1H); 2.22 (s, 3H); 0.26 (s,9H).

The above derivative (3.80 g, 13.7 mmol) and potassium carbonate (0.35g, 2.5 mmol) were stirred for 4 h with methanol (50 mL); methanol wasevaporated in vacuo and the residue was dissolved in dichloromethane andfiltered through a paddle of silica gel affording5-ethynyl-2-methylbenzo[b]thiophene-1,1-dioxide.

Yield: 2.10 g (74%).

M.p.: 165-166° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.65 (d, J=7.8 Hz, 1H); 7.53(d, J=7.8 Hz, 1H); 7.35 (s, 1H); 6.75 (s, 1H); 3.28 (s, 1H); 2.22 (s,3H).

The above aryl acetylene (251 mg, 1.23 mmol) and diisopropylamine (0.40mL, 2.85 mmol) were added to a solution of methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(350 mg, 0.614 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature over night, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, hexanes/ethyl acetate 4:1) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-(2-methyl-1,1-dioxobenzo[b]thiophen-5-ylethynyl)phenyl]allyloxy]-2-methylphenoxy]acetateas yellow solidifying oil.

Yield: 346 mg (87%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.70 (d, J=7.8 Hz, 1H); 7.61(d, J=1.2 Hz, 1H); 7.57 (d, J=8.4 Hz, 2H); 7.43 (s, 1H); 7.32 (d, J=8.5Hz, 2H); 7.24 (d, J=8.3 Hz, 2H); 7.19 (d, J=8.5 Hz, 2H); 6.79 (m, 1H);6.69 (d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.8Hz, 1H); 6.32 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz, 2H);3.79 (s, 3H); 2.25 (s, 3H); 2.24 (s, 3H); 1.31 (s, 9H).

To a solution of the above ester (339 mg, 0.524 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (72 mg, 1.72 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.098 mL; 1.71 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withethyl acetate (40 mL) and water (30 mL); the phases were separated andthe aqueous phase was extracted with ethyl acetate (3×20 mL).

The combined organic layers were washed with water (2×20 mL) and brine(2×20 mL). The organic solution was dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanes(2×4 mL) yielding the title acid as white solid.

Yield: 207 mg (63%).

M.p.: 104-116° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.70 (d, J=7.9 Hz, 1H); 7.60(m, 1H); 7.57 (d, J=8.1 Hz, 2H); 7.42 (s, 1H); 7.32 (d, J=8.4 Hz, 2H);7.24 (d, J=8.2 Hz, 2H); 7.19 (d, J=8.5 Hz, 2H); 6.78 (s, 1H); 6.69 (d,J=2.5 Hz, 1H); 6.66 (d, 1H); 6.59 (dd, J=9.0 and 2.8 Hz, 1H); 6.32 (t,J=6.7 Hz, 1H); 4.59 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 2.24 (s, 6H); 1.31(s, 9H).

Example 32(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(6-phenylpyridin-3-yl)allyloxy]-phenoxy]aceticAcid

2,5-Dibromopyridine (0.948 g, 4 mmol), phenylboronic acid (0.488 g, 4mmol) and tetrakis(triphenylphosphine)palladium (0.116 g, 0.1 mmol) weredissolved in anhydrous tetrahydrofuran (6 mL) and a solution of sodiumcarbonate (0.848 g, 8 mmol) in water (6 mL) was added. The mixture wasput under nitrogen and stirred at 75° C. for 16 h. The mixture wasconcentrated in vacuo. The residue was dissolved in water (10 mL) andextracted with dichloromethane (3×5 mL). The combined organic extractswere dried with anhydrous sodium sulphate. Column chromatography of theresidue (silica gel Fluka 60, hexanes/dichloromethane 1:1) afforded3-bromo-6-phenylpyridine as a white crystalline product.

Yield: 0.74 g (79%).

R_(F) (SiO₂, hexanes/dichloromethane 1:1): 0.30.

In nitrogen atmosphere, the above bromo derivative (0.468 g, 2 mmol),bis(triphenylphosphine)palladium(II) dichloride (0.042 g, 0.06 mmol) andcopper(I) iodide (0.011 g, 0.06 mmol) were dissolved in tetrahydrofuran(50 mL). Propargyl alcohol (0.14 mL, 2.4 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL, 2.4 mmol) were added viasyringe. Traces of air were removed; the mixture was stirred at ambienttemperature for 3 h and then at 50° C. for 16 h under nitrogen. Thereaction mixture was concentrated in vacuo; the residue was mixed withwater (8 mL) and extracted with dichloromethane (4×3 mL). The combinedorganic layers were dried with anhydrous sodium sulphate, concentratedin vacuo and the obtained residue was submitted to column chromatography(silica gel Fluka 60, hexanes/ethyl acetate 1:1) affording3-(6-phenylpyridin-3-yl)prop-2-yn-1-ol.

Sodium methoxide (2.5 mg, 0.045 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (1.43 mL, 1.43 mmol). Themixture was cooled to 0° C. and a solution of3-(6-phenylpyridin-3-yl)prop-2-yn-1-ol (300 mg, 1.43 mmol) intetrahydrofuran (6 mL) was slowly added. The reaction mixture wasstirred at 0° C. for 2 h and then at ambient temperature for 2 h. Thereaction mixture was cooled to 0° C. again, ethyl acetate (0.24 mL, 2.4mmol) was added and the mixture was stirred for further 10 min withoutcooling. 1,4-Diiodobenzene (527 mg, 1.60 mmol), anhydrous zinc chloride(108 mg, 1.23 mmol), tris(dibenzylideneacetone)dipalladium chloroformcomplex (29.5 mg, 0.029 mmol) and tri-(2-furyl)phosphine (26.6 mg, 0.118mmol) were added, the mixture was degassed and kept under argon. Themixture was heated at 60° C. for 20 h; methanol (0.7 mL) was added andthe mixture was stirred for additional 1 h. The reaction mixture wasdiluted with ether (30 mL) and subsequently saturated aqueous solutionof ammonium chloride (0.36 mL) was added. The formed suspension wasfiltered through a paddle of silica gel and the paddle was thoroughlywashed with ethyl acetate. The combined filtrates were concentrated invacuo and the residue was submitted to column chromatography (silica gelFluka 60, hexanes/ethyl acetate 1:1) affording(E)-3-(4-iodophenyl)-3-(6-phenylpyridin-3-yl)prop-2-en-1-ol.

Yield: 0.240 g (46%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.61 (d, J=1.9 Hz, 1H); 7.80(m, 2H); 7.73-7.41 (m, 7H); 6.94 (d, J=8.3 Hz, 2H); 6.34 (t, J=6.8 Hz,1H); 4.25 (bt, J=6.5 Hz, 2H).

The above allyl alcohol (238 mg, 0.0.65 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (140 mg, 0.715 mmol; example 2) andtriphenylphosphine (205 mg, 0.78 mmol) were dissolved in a mixture ofanhydrous toluene (8 mL) and tetrahydrofuran (6 mL). The mixture wascooled to 0° C., kept under argon and a degassed solution of diisopropylazodicarboxylate (0.163 mL, 0.78 mmol) in anhydrous tetrahydrofuran (1mL) was added dropwise during 10 min. The reaction mixture was allowedto warm up to ambient temperature with the bath and then was stirred for3 days. The solvents were evaporated in vacuo and the residue wassubmitted to flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 85:15) affording methyl(E)-[4-[3-(4-iodophenyl)-3-(6-phenylpyridin-3-yl)allyloxy]-2-methyl-phenoxy]acetateas oil.

Yield: 130 mg (35%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.60 (d, J=1.9 Hz, 1H); 7.99(d, J=6.8 Hz, 2H); 7.77-7.45 (m, 7H); 6.99 (d, J=8.2 Hz, 2H); 6.70-6.57(m, 3H); 6.41 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.53 (d, J=6.7 Hz, 2H);3.79 (s, 3H); 2.26 (s, 3H). 4-Propargylmorpholine (51 mg, 0.405 mmol)was added to a solution of the above iodo derivative (130 mg, 0.225mmol) in a mixture of tetrahydrofuran (3 mL) and triethylamine (3 mL).The mixture was degassed and copper(I) iodide (7 mg, 0.036 mmol) andtetrakis(triphenylphosphine)-palladium (21 mg, 0.018 mmol) were added.The reaction mixture was stirred at ambient temperature for 2 days,filtered and the filtrate was evaporated in vacuo. The residue waspurified by flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 4:6) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(6-phenylpyridin-3-yl)allyloxy]-phenoxy]acetateas oil.

Yield: 135 mg (89%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:9): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.60 (bs, 1H); 7.99 (d, J=7.0Hz, 2H); 7.72-7.26 (m, 7H); 7.19 (d, J=7.9 Hz, 2H); 6.69-6.60 (m, 3H);6.41 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.54 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 3.77 (m, 4H); 3.54 (s, 2H); 2.66 (bs, 4H); 2.26 (s, 3H).

To a solution of the above ester (115 mg, 0.20 mmol) intetrahydrofuran/methanol mixture (1:1.2 mL), a solution of lithiumhydroxide monohydrate (12 mg, 0.278 mmol) in distilled water (0.3 mL)was added under cooling (0° C.). The solution was stirred for 3 h atambient temperature, glacial acetic acid (0.060 mL) was added and themixture was stirred for further 10 min. The solution was diluted withchloroform (20 mL), washed with water (2×3 mL), dried with anhydrousmagnesium sulfate and evaporated in vacuo. The residue was trituratedwith hexanes (2×20 mL) yielding the title acid.

Yield: 104 mg (93%).

M.p.: 79-83° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₄): 11.46 (s, ˜2H); 8.67 (s, 1H);7.93-7.40 (m, ˜9H); 7.20 (d, J=8.1 Hz, 2H); 6.55-6.71 (m, 3H); 6.45 (t,J=6.7 Hz, 1H); 4.58 (s, 2H); 4.53 (d, J=6.7 Hz, 2H); 3.87 (m, 4H); 3.85(s, 2H); 3.04 (m, 4H); 2.26 (s, 3H).

Example 33(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(N-cyclopropylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

N-Cyclopropyl-N-(prop-2-ynyl)amine (105 mg, 1.103 mmol) was added to asolution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(336 mg, 0.613 mmol; prepared as described in example 7) in a mixture oftetrahydrofuran (5 mL) and triethylamine (5 mL). The mixture wasdegassed and copper(I) iodide (19 mg, 0.1 mmol) andtetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were added. Thereaction mixture was stirred at ambient temperature for 2 days, dilutedwith dichloromethane (40 mL), washed with water (2×15 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 7:3) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(N-cyclopropylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas oil.

Yield: 205 mg (65%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.0 Hz, 2H);7.27-7.11 (m, 6H); 6.69-6.54 (m, 3H); 6.27 (t, J=6.7 Hz, 1H); 4.58 (s,2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.77 (m, 2H); 2.24 (s, 3H);0.94 (m, 1H); 0.50 (m, 4H).

To a solution of the above ester (200 mg, 0.388 mmol) intetrahydrofuran/methanol mixture (1:1.6 mL), a solution of lithiumhydroxide monohydrate (24.4 mg, 0.58 mmol) in distilled water (0.5 mL)was added. The solution was stirred for 2 h at ambient temperature,glacial acetic acid (0.08 mL) was added and the mixture was stirred forfurther 10 min. The solution was diluted with dichloromethane (30 mL),washed with water (2×10 mL), dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was triturated with hexanes (2×20 mL)yielding the title acid.

Yield: 120 mg (62%).

M.p.: 92-95° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₄): 7.46-7.12 (m, 8H); 6.67-6.49(m, 3H); 6.30 (t, J=6.6 Hz, 1H); 4.55 (s, 2H); 4.46 (d, J=6.7 Hz, 2H);4.11 (s, 2H); 2.23 (s, 3H); 2.07 (m, 1H); 1.08 (m, 2H); 0.83 (s, 2H).

Example 34(E)-[2-Methyl-4-[3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-phenoxy]aceticAcid

To a degassed solution of 1-bromo-3-trifluoromethylbenzene (20.0 g, 88.8mmol) in tetrahydrofuran (160 ml) were in the following order added:copper(I) iodide (506 mg, 2.66 mmol),tetrakis(triphenylphosphine)palladium (3.06 g, 26.6 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (16.22 g, 106.6 mmol). The resultingmixture was degassed one more time, cooled in an ice bath and a solutionof propargyl alcohol (5.94 g, 106.6 mmol) in tetrahydrofuran (10 mL) wasadded over period of 20 min. The reaction mixture was slowly heated upto 55° C. and then stirred at this temperature for 16 h. The mixture wasdiluted with diethyl ether (400 mL), washed with water (100 mL), 5%hydrochloric acid (100 mL) and saturated aqueous solution of sodiumhydrogen carbonate (80 mL). The organic solution was dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, hexanes/ethylacetate 85:15) affording 3-(3-trifluoromethylphenyl)prop-2-yn-1-ol.

Yield: 4.40 g (50%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.70 (s, 1H); 7.59 (t, J=7.8Hz, 2H); 7.44 (t, J=7.8 Hz, 1H); 4.52 (d, J=6.1 Hz, 2H); 1.89 (t, J=6.1Hz, 1H).

Sodium methoxide (90 mg, 1.67 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (33 mL, 33 mmol) under argon. Themixture was cooled to 0° C. and a solution of the above alcohol (6.7 g,33.5 mmol) in tetrahydrofuran (25 mL) was added over 10 min. Thereaction was stirred at 0° C. for 3 h; dry ethyl acetate (10 mL, 103mmol) was added and the whole mixture was stirred at ambient temperaturefor 15 min. A degassed solution of 1,4-diiodobenzene (13.25 g, 40.1mmol) in dry tetrahydrofuran (25 mL), anhydrous zinc chloride (2.73 g,20.0 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex(0.692 g, 0.66 mmol), and tri(2-furyl)phosphine (0.854 g, 3.6 mmol) wereadded; the mixture was degassed and then was heated at 60° C. for 15 hunder argon. The suspension was cooled down; methanol (16 mL) was addedand the mixture was stirred for additional 1 h. The reaction was dilutedwith ether (350 mL) and saturated aqueous solution of ammonium chloride(9 mL) was added. The mixture was filtered through a paddle of silicagel and the paddle was thoroughly washed with ether (100 mL). Thesolvents were evaporated in vacuo and the residue was purified by flashcolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 5:1)affording (E)-3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)prop-2-en-1-olas solidifying oil.

Yield: 4.14 mg (31%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=7.4 Hz, 2H); 7.82(m, 2H); 7.33 (m, 2H); 6.91 (m, 2H); 6.28 (t, J=6.8 Hz, 1H); 4.22 (m,2H).

The above allyl alcohol (2.0 g, 4.94 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.08 g, 5.54 mmol; example 2) andtriphenylphosphine (1.50 g, 6.02 mmol) were dissolved in a mixture ofanhydrous toluene (40 mL) and tetrahydrofuran (20 mL). The mixture wascooled to 0° C., kept under argon and a degassed solution of diisopropylazodicarboxylate (1.15 mL, 5.82 mmol) in anhydrous tetrahydrofuran (10mL) was added dropwise during 10 min. The reaction mixture was allowedto warm up to ambient temperature with the bath and then was stirred for20 h. The solvents were evaporated in vacuo and the residue wassubmitted to flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 9:1) affording methyl(E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]acetateas yellow oil.

Yield: 1.99 g (69%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.74 (d, J=8.3 Hz, 2H); 7.53(m, 2H); 7.41 (m, 2H); 6.95 (d, J=8.3 Hz, 2H); 6.68-6.56 (m, 3H); 6.36(t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.50 (d, J=6.7 Hz, 2H); 3.79 (s, 3H);2.26 (s, 3H).

A solution of the above ester (400 mg, 0.68 mmol) in a mixture oftetrahydrofuran (12 mL) and triethylamine (12 mL) was degassed and1-propargylpyrazole (144 mg, 1.36 mmol) was added in argon atmosphere.The solution was cooled down; tetrakis(triphenylphosphine)palladium (62mg, 0.054 mmol) and copper(I) iodide (20 mg, 0.108 mmol) were added andthe resulting mixture was stirred at ambient temperature for 30 h. Themixture was evaporated in vacuo; the residue was dissolved in ethylacetate (20 mL) and the formed solution was washed with water (2×15 mL)and brine (10 mL). The organic solution was dried with anhydrousmagnesium sulfate and evaporated in vacuo. The residue was purified byflash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate7:3) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-phenoxy]acetate.

Yield: 287 mg (75%).

RF (SiO₂, hexanes/ethyl acetate 3:1): 0.15.

1H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (d, J=2.3 Hz, 1H);7.57-7.37 (m, 7H); 7.16 (d J=8.3 Hz, 2H); 6.68-6.55 (m, 3H); 6.36 (t,J=6.7 Hz, 1H); 6.34 (m, 1H); 5.20 (s, 2H); 4.58 (s, 2H); 4.51 (d, J=6.7Hz, 2H); 3.79 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (265 mg, 0.47 mmol) intetrahydrofuran/methanol mixture (1:5, 11 mL), a solution of lithiumhydroxide monohydrate (39.6 mg, 0.945 mmol) in distilled water (1 mL)was added under cooling to 0° C. The solution was stirred for 1 h undercooling and 2 h at ambient temperature. The solution was acidified withacetic acid (0.054 mL, 0.945 mmol) and evaporated in vacuo. The residuewas dissolved in ethyl acetate (40 mL); the solution was washed withwater (2×15 mL), brine (10 mL), dried with anhydrous magnesium sulfateand evaporated in vacuo. The residue was triturated with hexanesyielding the title acid as tan solid.

Yield: 118 mg (45%).

M.p.:

(foam).

R_(F) (SiO₂, chloroform/methanol 9:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (m, 1H); 7.60-7.39 (m,˜7H); 7.14 (d, J=8.1 Hz, 2H); 6.68-6.53 (m, 3H); 6.36 (t, J=6.7 Hz, 1H);6.33 (m, 1H); 5.23 (s, 2H); 4.61 (s, 2H); 4.50 (d, J=6.7 Hz, 2H); 2.25(s, 3H).

Example 35(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]aceticAcid

N-Propargylmorpholine (171 mg, 1.37 mmol) was added to a solution ofmethyl(E)[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.68 mmol; prepared as described in example 34) in a mixture oftetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture wasdegassed and copper(I) iodide (20 mg, 0.108 mmol) andtetrakis(triphenylphosphine)-palladium (62 mg, 0.054 mmol) were added.The reaction mixture was degassed once more and then stirred at ambienttemperature for 2 days under argon. The mixture was evaporated in vacuo;the residue was dissolved in ethyl acetate (50 mL) and the solution waswashed with water (2×15 mL) and brine (10 mL). The organic solution wasdried with anhydrous magnesium sulfate and its evaporation gave oil thatwas purified by flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 1:1) yielding methyl(E)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyl-oxy]phenoxy]acetateas oil.

Yield: 382 mg (95%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.10.

1H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.58-7.40 (m, 6H); 7.15 (d,J=8.2 Hz, 2H); 6.69-6.56 (m, 3H); 6.35 (t, J=6.6 Hz, 1H); 4.59 (s, 2H);4.52 (d, J=6.6 Hz, 2H); 3.80 (s, 3H); 3.78 (m, 4H); 3.54 (s, 2H); 2.66(m, 4H); 2.25 (s, 3H).

To a solution of the above ester (367 mg, 0.633 mmol) intetrahydrofuran/methanol mixture (5:1, 11 mL), a solution of lithiumhydroxide monohydrate (53 mg, 0.126 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2 h at ambienttemperature, glacial acetic acid (0.072 mL) was added and the mixturewas stirred for further 10 min. The solution was diluted with diethylether (20 mL), the solution was washed with water (2×15 mL, brine (10mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (2×20 mL) yielding the title acid.

Yield: 168 mg (47%).

M.p.: 61-70° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55-7.34 (m, ˜6H); 7.12 (m,2H); 6.68-6.60 (m, 3H); 6.37 (t, J=6.7 Hz, 1H); 4.54 (s, 2H); 4.48 (d,J=6.7 Hz, 2H); 3.84 (m, 4H); 3.73 (s, 2H); 2.91 (m, 4H); 2.25 (s, 3H).

Example 36(E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]aceticAcid

1-Propargylpiperidin-4-ol (191 mg, 1.374 mmol) and diisopropylamine(0.45 mL, 3.23 mmol) were added to a solution of methyl(E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)-allyloxy]-2-methylphenoxy]acetate(400 mg, 0.687 mmol; prepared as described in example 34) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10.4 mg, 0.055 mmol) and bis(triphenylphosphine)palladium(II)dichloride (24.1 mg, 0.034 mmol) were added. The reaction mixture wasstirred at ambient temperature for 20 h and evaporated in vacuo. Theresidue was purified by flash column chromatography (silica gel Fluka60, chloroform/methanol 96:4) yielding methyl(E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 420 mg (99%).

R_(F) (SiO₂, chloroform/methanol 9:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55-7.39 (m, 6H); 7.14 (d,J=8.3 Hz, 2H); 6.69-6.55 (m, 3H); 6.35 (t, J=6.6 Hz, 1H); 4.57 (s, 2H);4.52 (d, J=6.6 Hz, 2H); 3.79 (s, 3H); 3.54 (s, 2H); 2.88 (m, 2H); 2.44(m, 2H); 2.25 (s, 3H); 1.98 (m, 2H); 1.68 (m, 2H).

To a solution of the above ester (404 mg, 0.68 mmol) intetrahydrofuran/methanol mixture (4:1, 15 mL), a solution of lithiumhydroxide monohydrate (57 mg, 1.3 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred for 2 h undercooling, glacial acetic acid (0.065 mL) was added and the mixture wasstirred for further 10 min. The solution was diluted with ether (40 mL)and water (15 mL); the phases were separated and the organic phase waswashed with water (2×15 mL), dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was triturated with hexanes (2×10 mL)yielding the title acid as pale solid.

Yield: 147 mg (37%).

M.p.: 82-91° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₄, δ_(H)): 10.13 (bs, ˜4H);7.55-7.39 (m, 6H); 7.14 (d, J=8.2 Hz, 2H); 6.70-6.46 (m, 3H); 6.38 (t,J=6.8 Hz, 2H); 4.52 (s, 2H); 4.45 (d, J=6.8 Hz, 2H); 4.08 (s, 2H); 3.99(bs, 1H); 3.49 (m, 2H); 3.22 (m, 2H); 2.23 (s, 3H); 2.12 (m, 2H); 1.93(m, 2H).

Example 37(E)-[4-[3-[4-[3-(N,N-Dimethylamino)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methyl-phenoxy]aceticAcid

Dimethyl(prop-2-ynyl)amine (114 mg, 1.374 mmol) was added to a solutionof methyl(E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate(400 mg, 0.687 mmol; prepared as described in example 34) in a mixtureof tetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture wasdegassed and copper(I) iodide (20 mg, 0.109 mmol) andtetrakis(triphenylphosphine)palladium (63 mg, 0.054 mmol) were added.The reaction mixture was stirred at ambient temperature for 24 h.Further portions of dimethyl(prop-2-ynyl)amine (57 mg, 0.687 mmol),copper(I) iodide (10 mg, 0.0545 mmol) andtetrakis(triphenylphosphine)palladium (31.5 mg, 0.027 mmol) were addedand the reaction mixture was stirred under argon for additional 20 h.The mixture was evaporated in vacuo; the residue was dissolved in ethylacetate (30 mL) and was washed with water (2×15 mL) and brine (10 mL).The organic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 3:5) yieldingmethyl(E)-[4-[3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetateas oil.

Yield: 230 mg (62%).

R_(F) (SiO₂, hexanes/ethyl acetate 1:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.52-7.39 (m, 6H); 7.14 (d,J=8.3 Hz, 2H); 6.69-6.57 (m, 3H); 6.35 (t, J=6.7 Hz, 1H); 4.59 (s, 2H);4.52 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.50 (s, 2H); 2.39 (s, 6H); 2.25(s, 3H).

To a solution of the above ester (218 mg, 0.40 mmol) intetrahydrofuran/methanol mixture (4:1, 11 mL), a solution of lithiumhydroxide monohydrate (34 mg, 0.81 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred at ambienttemperature for 2 h. Glacial acetic acid (0.046 mL) was added and themixture was stirred for further 10 min. The solution was diluted withether (30 mL), washed with water (2×15 mL) and brine (10 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue wastriturated with hexanes (2×10 mL) yielding the title acid as pale solid.

Yield: 147 mg (37%).

M.p.: 55-64° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₄, δ_(H)): 7.55-7.34 (m, ˜6H);7.12 (m, ˜2H); 6.69-6.52 (m, 3H); 6.40 (t, J=6.6 Hz, 1H); 4.57 (s, 2H);4.49 (d, J=6.7 Hz, 2H); 4.17 (s, 2H); 2.90 (s, 6H); 2.25 (s, 3H).

Example 38(Z)-[4-[3-(4-Cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

To a degassed solution of 1-bromo-4-cyclopropylbenzene (4.4 g, 22.3mmol; prepared according to J. Org. Chem. 1976, 41, 2262) in anhydroustetrahydrofuran (22 mL), copper(I) iodide (134 mg, 0.70 mol) andtetrakis(triphenylphosphine)palladium (773 mg, 0.67 mmol) were added andthe mixture was cooled down with ice bath.1,8-Diazabicyclo[5.4.0]-undec-7-ene (4 mL, 26.8 mmol) was added and thereaction mixture was degassed again. A degassed solution ofprop-2-yn-1-ol (1.56 mL, 26.8 mmol) in anhydrous tetrahydrofuran (3 mL)was added dropwise afterwards and the reaction mixture was stirred at50° C. over night under nitrogen. After cooling, the mixture was dilutedwith ether (100 mL) and washed with water (40 mL) and 15% hydrochloricacid (2×40 mL). The aqueous layer was extracted with ether (5×40 mL).Combined organic extracts were finally washed with 10% aqueous solutionof sodium hydrogen carbonate (40 mL) and brine (2×40 mL) and dried withanhydrous magnesium sulfate. The crude product was purified by columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1)yielding 3-(4-cyclopropylphenyl)prop-2-yn-1-ol as yellow oil, whichsolidified in refrigerator.

Yield: 1.30 g (34%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.34 (d, J=8.2 Hz, 2H); 7.02(d, J=8.2 Hz, 2H); 4.51 (d, J=6.1 Hz, 2H); 1.90 (m, 1H); 1.69 (t, J=6.1Hz, 1H); 1.01 (m, 2H); 0.73 (m, 2H).

1 M Solution of lithium aluminum hydride in tetrahydrofuran (11.3 mL,11.3 mmol) was added to sodium methoxide (19 mg, 0.350 mmol) undernitrogen. The mixture was cooled to 0° C. and a solution of the abovehydroxy derivative (1.30 g, 7.50 mmol) in dry tetrahydrofuran (12 mL)was added dropwise. The reaction mixture was stirred at 0° C. for 3.5 h;dry ethyl acetate (2.25 mL, 22.9 mmol) was added and the whole mixturewas stirred at ambient temperature for 30 min. A degassed solution of1,4-diiodobenzene (2.47 g, 7.50 mmol) in anhydrous tetrahydrofuran (12mL), anhydrous zinc chloride (0.611 g, 4.53 mmol),tris(dibenzylidene-acetone)dipalladium chloroform complex (0.165 g, 0.16mmol) and tri-(2-furyl)phosphine (0.191 g, 0.82 mmol) were added; themixture was degassed and stirred at 65° C. for 22 h under atmosphere ofnitrogen. The suspension was cooled down; methanol (3.5 mL) was addedand the mixture was stirred for additional 1 h. After dilution withether (40 mL) and saturated aqueous solution of ammonium chloride (2mL), the mixture was filtered through a paddle of silica gel and thepaddle was thoroughly washed with ether (80 mL). Solvents wereevaporated in vacuo and the residue was separated by flash columnchromatography (silica gel Fluka 60, dichloromethane/ethyl acetate 20:1)affording (Z)-3-(4-cyclopropylphenyl)-3-(4-iodophenyl)prop-2-en-1-ol asyellow oil, which solidifies at 0° C.

Yield: 0.98 g (35%).

R_(F) (SiO₂, dichloromethane/ethyl acetate 20:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.3 Hz, 2H); 7.14(d, J=8.4 Hz, 2H); 7.01 (d, J=8.3 Hz, 2H); 6.93 (d, J=8.3 Hz, 2H); 6.22(t, J=6.9 Hz, 1H); 4.20 (m, 2H); 1.90 (m, 1H); 1.49 (t, J=5.4 Hz, 1H);0.99 (m, 2H); 0.71 (m, 2H).

The above allyl alcohol (0.98 g, 2.60 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.545 g, 2.78 mmol; compoundVUFB-21004) and triphenylphosphine (0.782 g, 2.98 mmol) were dissolvedin a mixture of anhydrous toluene (12 mL) and tetrahydrofuran (4 mL).The mixture was cooled to 0° C., kept under nitrogen and a degassedsolution of diisopropyl azodicarboxylate (0.587 mL, 2.98 mmol) inanhydrous tetrahydrofuran (5 mL) was added dropwise. The reactionmixture was allowed to warm up to ambient temperature and then wasstirred over night. The solvents were evaporated in vacuo and theresidue was submitted to flash column chromatography (silica gel Fluka60, hexanes/ethyl acetate 8:1) affording methyl(Z)-[4-[3-(4-cyclopropylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]-acetateas solid mass.

Yield: 890 mg (62%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.73 (d, J=8.2 Hz, 2H); 7.14(d, J=8.2 Hz, 2H); 7.00 (d, J=8.2 Hz, 2H); 6.94 (d, J=8.2 Hz, 2H); 6.70(d, J=2.5 Hz, 1H); 6.65 (d, J=8.8 Hz, 1H); 6.59 (dd, J=8.8 and 2.7 Hz,1H); 6.28 (t, J=6.7 Hz, 1H); 4.60 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.81(s, 3H), 2.27 (s, 3H); 1.89 (m, 1H); 0.99 (m, 2H); 0.71 (m, 2H).

To a degassed solution of the above ester (392 mg, 0.707 mmol),N-propargylmorpholine (176 mg, 1.41 mmol) and diisopropyl amine (0.466mL, 3.3 mmol) in anhydrous tetrahydrofuran (11 mL),bis(triphenylphosphine)palladium(II) dichloride (37 mg, 0.053 mmol) andcopper(I) iodide (12.0 mg, 0.063 mmol) were added. The reaction mixturewas stirred at ambient temperature for 7 h under nitrogen. The solventswere evaporated in vacuo and the residue was purified by flash columnchromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5)yielding methyl(Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 370 mg (95%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.14(d, J=8.0 Hz, 2H); 7.13 (d, J=8.1 Hz, 2H); 6.98 (d, J=8.2 Hz, 2H); 6.67(d, J=2.5 Hz, 1H); 6.62 (d, J=8.8 Hz, 1 H); 6.56 (dd, J=8.9 and 2.8 Hz,1H); 6.26 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.78(m, 7H); 3.53 (s, 2H); 2.66 (t, J=4.5 Hz, 4H); 2.24 (s, 3H); 1.87 (m,1H); 0.97 (m, 2H); 0.69 (m, 2H).

The above ester (360 mg, 0.65 mmol) was dissolved in a mixture oftetrahydrofuran (10 mL) and methanol (5 mL) and a solution of lithiumhydroxide monohydrate (62 mg, 1.47 mmol) in distilled water (2.5 mL) wasadded. The mixture was stirred over night and then diluted withsaturated aqueous solution of ammonium chloride (53 mL). The resultingmixture was extracted with ether (3×50 mL); the organic layers werecombined, dried with anhydrous magnesium sulfate and evaporated invacuo. The residue was triturated with hexanes (2×10 mL) yielding thetitle acid as white powder.

Yield: 177 mg (51%).

M.p.: 178-182° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.15(d, J=8.1 Hz, 2H); 7.13 (d, J=8.2 Hz, 2H); 6.99 (d, J=8.3 Hz, 2H); 6.68(d, J=2.8 Hz, 1H); 6.66 (d, J=8.8 Hz, 1H); 6.54 (dd, J=8.8 Hz; 2.9 Hz,1H); 6.28 (t, J=6.8 Hz, 1H); 4.60 (s, 2H); 4.48 (d, J=6.8 Hz, 2H); 3.88(t, J=4.6 Hz, 4H); 3.81 (s, 2H); 3.00 (t, J=4.5 Hz, 4H); 2.24 (s, 3H);1.88 (m, 1H); 0.98 (m, 2H); 0.70 (m, 2H).

Example 39(Z)-[4-[3-(4-Cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

To a degassed solution of the ester (486 mg, 0.877 mmol; prepared asdescribed in example 38), 1-(N,N-dimethylamino)prop-2-yne (150 mg, 1.80mmol) and diisopropyl amine (0.589 mL, 4.24 mmol) in anhydroustetrahydrofuran (12 mL), bis(triphenylphosphine)palladium(II) dichloride(47 mg, 0.067 mmol) and copper(I) iodide (14.0 mg, 0.074 mmol) wereadded. The reaction mixture was stirred at ambient temperature for 6 hunder nitrogen. The solvents were evaporated in vacuo and the residuewas purified by flash column chromatography (silica gel Fluka 60,chloroform/methanol 100:0-95:5) yielding methyl(Z)-[4-[3-(4-cyclopropylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 431 mg (96%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.47 (d, J=8.3 Hz, 2H); 7.16(d, J=8.3 Hz, 2H); 7.14 (d, J=8.3 Hz, 2H); 7.00 (d, J=8.3 Hz, 2H); 6.69(d, J=2.7 Hz, 1H); 6.64 (d, J=8.8 Hz, 1H); 6.58 (dd, J=8.8 and 2.8 Hz,1H); 6.27 (t, J=6.7 Hz, 1H); 4.60 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 3.81(s, 3H); 3.51 (s, 2H); 2.40 (s, 6H); 2.26 (s, 3H); 1.89 (m, 1H); 0.98(m, 2H); 0.70 (m, 2H).

The above ester (420 mg, 0.824 mmol) was dissolved in a mixture oftetrahydrofuran (14 mL) and methanol (7 mL) and a solution of lithiumhydroxide monohydrate (78 mg, 1.85 mmol) in distilled water (3 mL) wasadded. The mixture was stirred over night and then diluted withsaturated aqueous solution of ammonium chloride (68 mL). The resultingmixture was extracted with ether (3×60 mL); the organic layers werecombined, dried with anhydrous magnesium sulfate and evaporated invacuo. The residue was triturated with hexanes yielding the title acidas white powder.

Yield: 267 mg (65%).

M.p.: 130-134° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.47 (d, J=8.1 Hz, 2H); 7.18(d, J=8.1 Hz, 2H); 7.13 (d, J=8.2 Hz, 2H); 6.99 (d, J=8.3 Hz, 2H); 6.68(d, J=2.8, 1H); 6.64 (d, J=8.9 Hz, 1H); 6.53 (dd, J=8.9 and 2.9 Hz, 1H);6.30 (t, J=6.8 Hz, 1H); 4.56 (s, 2H); 4.45 (d, J=6.8 Hz, 2H); 4.15 (s,2H); 2.88 (s, 6H); 2.24 (s, 3H); 1.88 (m, 1H); 0.98 (m, 2H); 0.70 (m,2H)

Example 40(E)-[2-Methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]phenoxy]aceticAcid

To a degassed solution of 4-bromothioanisole (10.15 g, 50.0 mmol) intetrahydrofuran (50 mL) were in the following order added: copper(I)iodide (286 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium (1.73g, 1.5 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (9.05 mL, 60.0mmol). The resulting mixture was degassed one more time and a solutionof propargyl alcohol (3.5 mL, 60.0 mmol) in tetrahydrofuran (5 mL) wasadded over period of 10 min. The reaction mixture was slowly heated upto 50° C. and then stirred at this temperature over night (˜20 h). Themixture was diluted with ether (350 mL) and 5% hydrochloric acid (100mL) was added. The mixture was filtered and the phases were separated.The aqueous phase was extracted with ether (2×60 mL) and collectedethereal solutions were washed with 1 M hydrochloric acid (30 mL) andsaturated aqueous solution of sodium hydrogen carbonate (2×50 mL), driedwith anhydrous magnesium sulfate and evaporated in vacuo. The residuewas purified by column chromatography (silica gel Fluka 60, chloroform)affording 3-(4-methylsulfanylphenyl)prop-2-yn-1-ol.

Yield: 8.5 g (95%).

R_(F) (SiO₂, chloroform): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.35 (d, J=8.5 Hz, 2H); 7.18(d, J=8.5 Hz, 2H); 4.50 (d, J=4.9 Hz, 2H); 2.49 (s, 3H); 1.94 (m, 1H).

Sodium methoxide (106 mg, 2 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (43.8 mL, 43.8 mmol) under argon.The mixture was cooled to 0° C. and a solution of the above hydroxyderivative (7.8 g, 43.8 mmol) in tetrahydrofuran (100 mL) was added over30 min. The reaction mixture was stirred at 0° C. for 3 h; dry ethylacetate (7.1 mL, 72 mmol) was added and the whole mixture was stirred atambient temperature for further 20 min. A degassed solution of1,4-diiodobenzene (20.2 g, 61.3 mmol) in dry tetrahydrofuran (30 mL),anhydrous zinc chloride (3.58 g, 26.3 mmol),tris(dibenzylidene-acetone)dipalladium chloroform complex (0.91 g, 0.875mmol), and tri-2-furylphosphine (0.813 g, 3.5 mmol) were added; themixture was degassed and then heated at 55° C. for 20 h under argon. Thesuspension was cooled down; methanol (22 mL) was added and the mixturewas stirred for additional 1 h. The reaction mixture was diluted withether (450 mL) and saturated aqueous solution of ammonium chloride (11mL) was added. The mixture was filtered through a paddle of silica geland the paddle was thoroughly washed with ether (150 mL). Solvents wereevaporated in vacuo and the residue was separated by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1)affording (Z)-3-(4-iodophenyl)-3-(4-methylsulfanylphenyl)prop-2-en-1-olas solidifying oil.

Yield: 5.45 g (33%).

M.p.: 91-95° C.

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.3 Hz, 2H); 7.15(m, 4H); 6.91 (d, J=8.3 Hz, 2H); 6.22 (t, J=6.9 Hz, 1H); 4.19 (d, J=6.9Hz, 2H); 2.47 (s, 3H); 1.53 (bs, 1H).

The above allyl alcohol (4.97 g, 13.0 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (2.81 g, 14.3 mmol; example 2) andtriphenylphosphine (4.09 g, 15.6 mmol) were dissolved in a mixture ofanhydrous toluene (200 mL) and tetrahydrofuran (75 mL). The mixture wascooled to 0° C., kept under argon and a degassed solution of diisopropylazodicarboxylate (3.32 mL, 15.6 mmol) in anhydrous tetrahydrofuran (25mL) was added dropwise during 30 min. The reaction mixture was allowedto warm up the ambient temperature with the bath and then was stirredfor 2 days. The solvents were evaporated in vacuo and the residue wassubmitted to flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 9:1) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-methylsulfanyl-phenyl)allyloxy]-2-methyl-phenoxy]acetateas solid mass.

Yield: 3.95 g (54%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.0 Hz, 2H); 7.15(m, 4H); 6.94 (d, J=8.0 Hz, 2H); 6.67-6.34 (m, 3H); 6.28 (t, J=6.6 Hz,1H); 4.58 (s, 2H); 4.47 (d, J=6.6 Hz, 2H); 3.79 (s, 3H); 2.47 (s, 3H);2.25 (s, 3H).

4-Propargylmorpholine (1.40 g, 2.50 mmol) was added to a solution of theabove iodo derivative (1.40 g, 2.50 mmol) in tetrahydrofuran (18 mL) andtriethylamine (18 mL). The mixture was degassed and copper(I) iodide (76mg, 0.40 mmol) and tris(triphenylphosphine)palladium (231 mg, 0.20 mmol)were added. The reaction mixture was stirred under argon at ambienttemperature for 20 h, filtered and the filtrate was evaporated in vacuo.The residue was purified by flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 2:1) yielding methyl(E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]-phenyl]allyloxy]phenoxy]acetate.

Yield: 1.62 g (97%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.36(m, 2H); 7.14 (d, J=8.2 Hz, 2H); 6.67-6.54 (m, 3H); 6.28 (t, J=6.7 Hz,1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.80 (s, 3H); 3.77 (m, 4H);3.53 (s, 2H); 2.66 (m, 4H); 2.47 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (1.36 g, 2.44 mmol) intetrahydrofuran/methanol mixture (1:2, 60 mL), a solution of lithiumhydroxide monohydrate (0.205 g, 4.88 mmol) in distilled water (6 mL) wasadded. The solution was stirred for 2 h at ambient temperature andacetic acid (0.56 mL; 9.8 mmol) was added. The resulting mixture wasstirred for further 10 min and then evaporated in vacuo. The residue wasdissolved in chloroform (80 mL), washed with water (2×20 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo.

The residue was triturated with hexanes (3×15 mL) yielding the titleacid as tan solid.

Yield: 925 mg (68%).

M.p.: 179-184° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.49 (d, J=8.1 Hz, 2H); 7.16(m, 6H); 6.68-6.54 (m, 3H); 6.31 (t, J=6.8 Hz, 1H); 4.60 (s, 2H); 4.48(d, J=6.8 Hz, 2H); 4.04 (s, 2H); 3.95 (m, 4H); 3.25 (m, 4H); 2.47 (s,3H); 2.24 (s, 3H).

Example 41(E)-[2-Methyl-4-[3-(4-methylsulfinylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]aceticAcid

30% Aqueous hydrogen peroxide (0.0613 mL, 0.6 mmol) was added to asolution of(E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-phenoxy]aceticacid (272 mg, 0.5 mmol; example 40) in glacial acetic acid (7 mL) at 5°C. under stirring. The mixture was left to stand over night at ambienttemperature, diluted with water and extracted with ethyl acetate (2×30mL). The collected extracts were alkalized with 15% solution of ammoniumhydroxide; the solution was decanted from the separated oil and the oilwas and dissolved in chloroform (45 mL). The solution was washed withwater (2×10 mL), dried with anhydrous magnesium sulphate and evaporatedin vacuo. The residue was triturated with hexanes (3×15 mL) to yield thetitle compound as pale solid.

Yield: 162 mg (58%).

M.p.: 137-142° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 4:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, AcOH-d₄, δ_(H)): 7.61 (d, J=8.3 Hz,2H); 7.49 (d, J=8.0 Hz, 2H); 7.41 (d, J=8.3 Hz, 2H); 7.16 (d, J=8.0 Hz,2H); 6.68-6.53 (m, 3H); 6.40 (t, J=6.6 Hz, 1H); 4.55 (s, 2H); 4.52 (d,J=6.6 Hz, 2H); 3.91 (s, 2H); 3.10 (m, 4H); 3.25 (m, 4H); 2.81 (s, 3H);2.24 (s, 3H).

Example 42(E)-[2-Methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethylphenyl)-allyloxy]phenoxy]aceticAcid

2-Ethynyl-5-methylthiophene (176 mg, 1.442 mmol) and diisopropylamine(0.475 mL, 3.39 mmol) were added to a solution of methyl(E)-[4-[3-(4-iodophenyl)-3-(3-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetate(420 mg, 0.721 mmol; prepared as described in example 34) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(11.0 mg, 0.0576 mmol) and bis(triphenylphosphine)palladium(II)dichloride (25.3 mg, 0.0361 mmol) were added. The reaction mixture wasstirred at ambient temperature for 20 h and evaporated in vacuo. Theresidue was purified by flash column chromatography (silica gel Flu ka60, hexanes/ethyl acetate 19:1) yielding methyl(E)-[2-methyl-4-[3-[4-[(5-methylthiophen-2-yl)ethynyl]phenyl]-3-(3-trifluoromethylphenyl)allyloxy]phenoxy]acetateas yellow oil.

Yield: 291 mg (70%).

R_(F) (SiO₂, chloroform/methanol 9:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.53 (m, 4H); 7.41 (m, 2H);7.17 (d, J=8.3 Hz, 2H); 7.10 (d, J=3.6 Hz, 1H); 6.69-6.56 (m, 3H); 6.36(t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.53 (d, J=6.7 Hz, 2H); 3.79 (s, 3H);2.49 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (201 mg, 0.509 mmol) intetrahydrofuran/methanol mixture (4:1, 11 mL), a solution of lithiumhydroxide monohydrate (42.3 mg, 1.0 mmol) in distilled water (1 mL) wasadded under cooling (0° C.). The solution was stirred at ambienttemperature for 2 h, acidified with acetic acid (0.32 mL) and themixture was stirred for further 10 min. The solution was diluted withether (30 mL); the mixture was washed with water (2×15 mL) and brine (10mL), dried with anhydrous magnesium sulfate and evaporated in vacuo.

The residue was triturated with hexanes (2×10 mL) yielding the titleacid as pale solid.

Yield: 144 mg (51%).

M.p.: 129-134° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.53 (m, 4H); 7.41 (m, 2H);7.18 (d, J=8.2 Hz, 2H); 7.10 (d, J=3.6 Hz, 1H); 6.70-6.58 (m, 4H); 6.35(t, J=6.6 Hz, 1H); 4.62 (s, 2H); 4.54 (d, J=6.6 Hz, 2H); 2.49 (s, 3H);2.25 (s, 3H).

Example 43(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

1-(N,N-Dimethylamino)prop-2-yne (0.131 mL, 1.23 mmol) anddiisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of themethyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(350 mg, 0.614 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature over night, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas oil.

Yield: 263 mg (82%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.31(d, J=8.5 Hz, 2H); 7.18 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.2 Hz, 2H); 6.67(d, J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.8 Hz,1H); 6.29 (t, J=6.6 Hz, 1H); 4.58 (s, 2H); 4.50 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.51 (s, 2H); 2.39 (s, 6H); 2.24 (s, 3H); 1.31 (s, 9H).

To a solution of the above ester (255 mg, 0.485 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (61 mg, 1.45 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.083 mL; 1.45 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL). The combinedorganic layers were washed with water (2×20 mL) and brine (2×20 mL). Theorganic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was triturated with hexanes (2×4 mL)yielding the title acid as white solid.

Yield: 206 mg (83%).

M.p.: 165-173° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.1 Hz, 2H); 7.32(d, J=8.5 Hz, 2H); 7.20 (d, J=8.5 Hz, 2H); 7.15 (d, J=8.1 Hz, 2H); 6.70(d, J=2.8 Hz, 1H); 6.58 (d, J=8.4 Hz, 1H); 6.36 (m, 2H); 4.52 (s, 2H);4.38 (d, J=7.0 Hz, 2H); 3.86 (s, 2H); 2.67 (s, ˜6H); 2.25 (s, 3H); 1.31(s, 9H).

Example 44(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(4-methylpiperazin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Under nitrogen atmosphere, 1-methyl-4-propargylpiperazine (380 mg, 2.75mmol) was added to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(450 mg, 0.82 mmol; prepared as described in example 7) in a mixture oftetrahydrofuran (10 mL) and triethylamine (8 mL) The solution wascooled, tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) andcopper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixturewas stirred at ambient temperature for 48 h, diluted with benzene (100mL) and washed with water (2×50 mL). The organic solution was dried withanhydrous potassium carbonate and subsequently evaporated in vacuo. Theresidue was purified by column chromatography (silica gel Fluka 60,benzene/ethanol 1:0-1:2) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(4-methylpiperazin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.

Yield: 360 mg (80%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.1 Hz, 2H); 7.26(d, J=8.6 Hz, 2H); 7.16 (d, J=8.6 Hz, 2H); 7.12 (d, J=8.1 Hz, 2H); 6.67(d, J=2.4 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.4 Hz,1H); 6.28 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.56 (s, 2H); 2.77 (bs, 4H); 2.64 (bs, 4H); 2.38 (s, 6H); 2.25(s, 3H).

The above ester (0.36 g, 0.658 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 72 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas triturated with hexanes (2×20 mL) yielding the title compound asamorphous solid.

Yield: 0.30 g (86%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.0 Hz, 2H); 7.23(d, J=8.5 Hz, 2H); 7.13 (d, J=8.5 Hz, 2H); 6.99 (d, J=8.0 Hz, 2H); 6.61(d, J=2.7 Hz, 1H); 6.54 (d, J=9.0 Hz, 1H); 6.27 (m, 2H); 4.41 (m, 4H);3.61 (s, 2H); 3.10 (bs, 4H); 2.88 (s, 4H); 2.61 (s, 3H); 2.22 (s, 3H).

Example 45(E)-[4-[3-(4-Chlorophenyl)-3-[4-(3-[N-(2-hydroxyethyl)-N-methylamino]propynyl]phenyl]-allyloxy]-2-methylphenoxy]aceticAcid

N-(2-Hydroxyethyl)-N-propargylmethylamine (300 mg, 2.65 mmol) was addedunder nitrogen atmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(450 mg, 0.82 mmol; prepared as described in example 7) in a mixture oftetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooledto 0° C., tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) andcopper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixturewas stirred at ambient temperature for 48 h, dissolved in benzene (100mL), decanted and evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, benzene/ethylacetate1:0-0:1) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-(3-[N-(2-hydroxyethyl)-N-methylamino]-propynyl]-phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 360 mg (82%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.1 Hz, 2H); 7.26(d, J=8.5 Hz, 2H); 7.16 (d, J=8.5 Hz, 2H); 7.14 (d, J=8.1 Hz, 2H); 6.67(d, J=2.7 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.7 Hz,1H); 6.29 (t, J=6.7 Hz, 1H); 4.97 (bs, 2H); 4.58 (s, 2H); 4.49 (d, J=6.7Hz, 2H); 3.79 (s, 3H); 3.75 (bs, 2H); 2.87 (bs, 2H); 2.25 (s, 3H); 2.09(s, 1H).

The above ester (0.36 g, 0.674 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 72 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas purified by chromatography on silica gel (Fluka 60, ethylacetate/methanol 9:1-1:1) and the crude product was triturated withhexanes yielding the title compound as amorphous solid.

Yield: 0.22 g (63%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃ and CD₃COOD, δ_(H)): 7.52 (d, J=8.0 Hz,2H); 7.27 (d, J=8.4 Hz, 2H); 7.18 (m, 4H); 6.66 (m, 2H); 6.56 (dd, J=1.7and 8.7 Hz, 1H); 6.34 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.49 (d, J=6.7Hz, 2H); 4.36 (s, 2H); 4.02 (s, 2H); 3.43 (s, 2H); 3.02 (s, 3H); 2.23(s, 3H); 2.06 (s, 1H).

Example 46(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

4-Propargylmorpholine (320 mg, 2.4 mmol) was added under nitrogenatmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate(450 mg, 0.82 mmol; prepared as described in example 7) in a mixture oftetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooledto 0° C. and tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol)and copper(I) iodide (22 mg, 0.115 mmol) were added. The reactionmixture was stirred at ambient temperature for 72 h, diluted withbenzene (100 mL) and washed with water (2×50 mL). The organic solutionwas dried with anhydrous potassium carbonate and subsequently evaporatedin vacuo. The residue was purified by column chromatography (silica gelFluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-allyloxy]-2-methylphenoxy]acetatecontaminated with ca. 20% of 1,6-bis(morpholin-4-yl)-2,4-hexadiyne.

Yield: 500 mg (89% calculated on pure ester).

R_(F) (SiO₂, chloroform/ethanol 9:1): 0.65.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H), signals belonging to the ester):7.46 (d, J=8.1 Hz, 2H); 7.26 (d, J=8.6 Hz, 2H); 7.16 (d, J=8.6 Hz, 2H);7.13 (d, J=8.1 Hz, 2H); 6.67 (d, J=2.7 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H);6.56 (dd, J=8.8 and 2.7 Hz, 1H); 6.28 (t, J=6.7 Hz, 1H); 4.58 (s, 2H);4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.76 (m, 4H); 3.53 (s, 2H); 2.66(m, 4H); 2.25 (s, 3H).

The above mixture (0.47 g, 0.688 mmol) was dissolved in ethanol (30 mL),a solution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 72 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas purified by chromatography on silica gel (Fluka 60,chloroform/ethanol 20:1-1:1) yielding insufficiently pure title compoundthat was further purified using preparative HPLC on reverse phase column(gradient elution with 0.1% formic acid/acetonitrile). This afforded thepure title compound as amorphous solid.

Yield: 0.16 g (44%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.25(d, J=8.5 Hz, 2H); 7.13 (m, 4H); 6.65 (d, J=2.7 Hz, 1H); 6.62 (d, J=8.7Hz, 1H); 6.51 (dd, J=2.7 and 8.7 Hz, 1H); 6.29 (t, J=6.6 Hz, 1H); 4.52(s, 2H); 4.45 (d, J=6.6 Hz, 2H); 3.86 (bs, 4H); 3.80 (s, 2H); 2.99 (s,4H); 2.24 (s, 3H).

Example 47(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

4-Hydroxy-1-propargylpiperidine (280 mg, 2.01 mmol) was added undernitrogen atmosphere to a degassed solution of methyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(450 mg, 0.82 mmol; prepared as described in example 7) in a mixture oftetrahydrofuran (10 mL) and triethylamine (8 mL) The solution was cooledto 0° C.; tetrakis(triphenylphosphine)palladium (85 mg, 0.073 mmol) andcopper(I) iodide (22 mg, 0.115 mmol) were added. The reaction mixturewas stirred at ambient temperature for 72 h, diluted with benzene (100mL), decanted and evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, benzene/methanol 10:0-4:6)yielding methyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.

Yield: 390 mg (85%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.26(d, J=8.7 Hz, 2H); 7.16 (d, J=8.7 Hz, 2H); 7.13 (d, J=8.2 Hz, 2H); 6.67(d, J=2.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.56 (dd, J=8.7 and 2.7 Hz,1H); 6.28 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(m, 4H); 3.57 (s, 2H); 2.94 (m, 2H); 2.50 (m, 2H); 2.25 (s, 3H); 2.00(m, 2H); 1.70 (m, 2H).

The above ester (0.39 g, 0.696 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 72 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas triturated with hexanes yielding the title compound as amorphoussolid.

Yield: 0.34 g (89%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.1 Hz, 2H); 7.25(d, J=8.5 Hz, 2H); 7.15 (d, J=8.5 Hz, 2H); 7.09 (d, J=8.1 Hz, 2H); 6.64(d, J=2.5 Hz, 1H); 6.59 (d, J=8.9 Hz, 1 H); 6.41 (dd, J=8.9 and 2.5 Hz,1H); 6.30 (t, J=6.8 Hz, 1H); 4.47 (s, 2H); 4.40 (d, J=6.8 Hz, 2H); 3.82(m, 3H); 3.21 (m, 2H); 2.89 (m, 2H); 2.22 (s, 3H); 2.03 (m, 2H); 1.77(m, 2H).

Example 48(E)-[2-Methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]aceticAcid

1-Propargylpyrazole (0.530 g, 5.0 mmol) and diisopropylamine (1.6 mL,11.7 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-methylsulfanylphenyl)allyloxy]-2-methylphenoxy]acetate(1.40 g, 2.5 mmol; prepared as described in example 40) intetrahydrofuran (35 mL). The mixture was degassed and copper(I) iodide(38.0 mg, 0.2 mmol) and bis(triphenylphosphine)palladium(II) dichloride(87.5 mg, 0.12 mmol) were added. The reaction mixture was stirred atambient temperature for 20 h and evaporated in vacuo. The residue waspurified by flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 7:3) yielding methyl(E)-[2-methyl-4-[3-(4-methylsulfanylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-phenoxy]acetateas yellow oil.

Yield: 1.04 g (80%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (d, J=2.3 Hz, 1H); 7.57(d, J=1.7 Hz, 1H); 7.48 (d, J=8.2 Hz, 2H); 7.15 (m, 6H); 6.66 (t, J=2.0Hz, 1H); 6.29 (t, J=6.7 Hz, 1H); 5.20 (s, 2H); 4.58 (s, 3H); 4.47 (d,J=6.7 Hz, 2H); 3.79 (s, 3H); 2.47 (s, 3H); 2.24 (s, 3H).

To a solution of the above ester (1.02 g, 1.89 mmol) intetrahydrofuran/methanol mixture (5:1, 30 mL), a solution of lithiumhydroxide monohydrate (0.15 g, 3.78 mmol) in distilled water (5 mL) wasadded. The solution was stirred for 2 h at ambient temperature; theprecipitated solid was filtered and then suspended in 10% aqueoussolution of ammonium chloride (5 mL). Acetic acid was added (2 drops)and the mixture was extracted with chloroform (3×15 mL). The collectedextracts were washed with brine (15 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanes(2×15 mL) yielding the title acid as tan solid.

Yield: 564 mg (66%).

M.p.: 131-137° C.

R_(F) (SiO₂, chloroform/methanol 9:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₄, δ_(H)): 7.71 (d, J=2.2 Hz, 1H);7.59 (d, J=1.6 Hz, 1H); 7.16 (m, 6H); 7.14 (d, J=8.1 Hz, 2H); 6.68-6.55(m, 3H); 6.33 (t, J=2.1 Hz, 1H); 6.29 (t, J=6.8 Hz, 1H); 5.24 (s, 2H);4.61 (s, 2H); 4.68 (d, J=6.8 Hz, 2H); 2.47 (s, 3H); 2.24 (s, 3H).

Example 49(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]aceticAcid

Under nitrogen atmosphere, (1-propargylpiperidin-4-yl)methanol (122 mg,0.8 mmol) and diisopropylamine (370 mg, 0.56 mmol) were added to adegassed solution of methyl(Z)[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(220 mg, 0.4 mmol; prepared as described in example 7) intetrahydrofuran (15 mL). Subsequently,bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) andcopper(I) iodide (15 mg, 0.075 mmol) were added; the reaction mixturewas degassed again and then stirred under inert atmosphere at ambienttemperature over night. The reaction mixture was diluted with ethylacetate (20 mL) and filtered through a paddle of silica gel. The paddlewas thoroughly washed with ethyl acetate (4×20 mL) and the combinedfiltrates were concentrated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, chloroform/methanol 95:5) yieldingmethyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-[4-(hydroxymethyl)piperidin-1-yl]propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 210 mg (91%).

R_(F) (chloroform/methanol 85:15): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H);7.27-7.24 (m, overlapped); 7.19-7.12 (m, 4H); 6.67 (d, J=2.8 Hz, 1H);6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.9 and 2.8 Hz, 1H); 6.28 (t, J=6.7Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.58 (s,2H); 3.07 (d, J=11.3 Hz, 2H); 2.33 (t, J=11.8 Hz, 2H); 2.25 (s, 3H);2.08 (s, 3H); 1.82 (d, J=11.9 Hz, 2H); 1.47-1.38 (m, 3H).

The above ester (210 mg, 0.37 mmol) was dissolved in a mixture oftetrahydrofuran (5 mL) and methanol (2 mL). A solution of lithiumhydroxide monohydrate (36 mg, 0.73 mmol) in water (2 mL) was added andthe mixture was stirred for 2 h at ambient temperature. The reactionmixture was diluted with water (15 mL) and acidified with 2 Mhydrochloric acid to pH˜6. A saturated solution of ammonium chloride (5mL) was added and the mixture was extracted with ethyl acetate (4×15mL). The organic extracts were washed with 10% aqueous solution ofammonium chloride (2×20 mL) and brine (2×15 mL), dried with anhydrousmagnesium sulfate and subsequently evaporated in vacuo. The residue wastriturated with hexanes (2×10 mL) yielding the title compound asamorphous solid.

Yield: 95 mg (46%).

M.p.: 94-104° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 80:20): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.44 (d, J=8.0 Hz, 2H); 7.34(d, J=8.4 Hz, 2H); 7.17-7.12 (m, 4H); 6.64-6.53 (m, 3H); 6.29 (t, J=6.4Hz, 1H); 4.51 (bs, 2H); 4.40 (d, J=6.5 Hz, 2H); 3.51 (s, 2H); 3.18 (d,J=5.9 Hz, 2H); 2.88-2.84 (m, 2H); 2.21-2.17 (m, 2H); 2.08 (s, 3H);1.64-1.60 (m, 2H); 1.17-1.01 (m, 3H).

Example 50(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

4-Hydroxy-1-propargylpiperidine (171 mg, 1.23 mmol) and diisopropylamine(0.40 mL, 2.85 mmol) were added to a solution of the methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodohenyl)llyloxy]-2-methylphenoxy]acetate(350 mg, 0.614 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature over night, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, dichloromethane/methanol 97:3) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl]-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas white solid.

Yield: 216 mg (61%).

R_(F) (SiO₂, chloroform saturated with ammonia/methanol 97:3): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.3 Hz, 2H); 7.31(d, J=8.6 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.3 Hz, 2H); 6.67(d, J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.9 and 2.8 Hz,1H); 6.29 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.56 (s, 2H); 2.92 (m, 2H); 2.47 (m, 2H); 2.24 (s, 3H); 1.99(m, 2H); 1.69 (m, ˜2H); 1.31 (s, 9H).

To a solution of the above ester (209 mg, 0.359 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (45 mg, 1.07 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.062 mL; 1.08 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withethyl acetate (40 mL) and water (30 mL); the phases were separated andthe aqueous phase was extracted with ethyl acetate (3×20 mL). Thecombined organic layers were washed with water (2×20 mL) and brine (2×20mL). The organic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was triturated with hexanes (2×4 mL)yielding the title acid as yellow solid.

Yield: 34 mg (17%).

M.p.: 95-110° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.1 Hz, 2H); 7.31(d, J=8.5 Hz, 2H); 7.17 (d, J=8.5 Hz, 2H); 7.10 (d, J=8.1 Hz, 2H); 6.66(d, J=3.0 Hz, 1H); 6.57 (d, J=8.9 Hz, 1H); 6.34 (m, 2H); 4.50 (s, 2H);4.39 (d, J=7.0 Hz, 2H); 3.88 (m, 3H); 3.29 (m, 2H); 3.00 (m,overlapped); 2.22 (s, 3H); 2.08 (m, ˜2H); 1.85 (m, ˜2H); 1.30 (s, ˜9H(overlapped)).

Example 51(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-[N-(2-hydroxyethyl)-N-methylamino]propynyl]phenyl]-allyloxy]-2-methylphenoxy]aceticAcid

2-[N-Methyl-N-(2-propynyl)amino]ethanol (139 mg, 1.23 mmol) anddiisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)llyloxy]-2-methylphenoxy]acetate(350 mg, 0.614 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature for 72 h, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, dichloromethane/ethanol 97:3) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-[N-(2-hydroxyethyl)-N-methylmino]ropynyl]phenyl]-allyloxy]-2-methyl-phenoxy]acetateas brown oil.

Yield: 193 mg (57%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.2 Hz, 2H); 7.31(d, J=8.5 Hz, 2H); 7.18 (d, J=8.5 Hz, 2H); 7.17 (d, J=8.2 Hz, 2H); 6.68(d, J=2.6 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.7 and 2.8 Hz,1H); 6.29 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.64 (m, 2H); 3.63 (s, 2H); 2.72 (m, 2H); 2.44 (s, 3H); 2.24(s, 3H); 1.31 (s, 9H).

To a solution of the above ester (187 mg, 0.337 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (42 mg, 1.00 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1 h undercooling, acetic acid (0.057 mL; 1.00 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL).

The combined organic layers were washed with water (2×20 mL) and brine(2×20 mL). The organic solution was dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was triturated with hexanes(2×5 mL) yielding the title acid as white solid.

Yield: 139 mg (76%).

M.p.: 165-172° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃+AcOH-d₆, δ_(H)): 7.46 (d, J=8.1 Hz, 2H);7.32 (d, J=8.5 Hz, 2H); 7.18 (m, 4H); 6.67 (d, J=2.6 Hz, 1H); 6.63 (d,J=8.8 Hz, 1H); 6.52 (dd, J=8.8 and 2.9 Hz, 1H); 6.33 (t, J=6.8 Hz, 1H);4.55 (s, 2H); 4.45 (d, J=6.8 Hz, 2H); 4.26 (s, 2H); 3.98 (m, 2H); 3.33(m, 2H); 2.95 (s, 3H); 2.24 (s, 3H); 1.31 (s, 9H).

Example 52(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

N-Propargylpyrazole (130 mg, 1.23 mmol) and diisopropylamine (0.40 mL,2.85 mmol) were added to a solution of methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]cetate(350 mg, 0.614 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)alladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature over night, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, hexanes/ethyl acetate 4:1-3:1) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas brown oil.

Yield: 205 mg (61%).

R_(F) (SiO₂, dichloromethane/methanol 98:2): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=2.2 Hz, 1H); 7.57(d, J=1.6 Hz, 1H); 7.49 (d, J=8.3 Hz, 2H); 7.31 (d, J=8.6 Hz, 2H); 7.18(d, J=8.3 Hz, 2H); 7.17 (d, J=8.6 Hz, 2H); 6.67 (d, J=2.8 Hz, 1H); 6.62(d, J=8.8 Hz, 1H); 6.56 (dd, J=8.9 and 2.8 Hz, 1H); 6.33 (m, 1H); 6.30(t, J=6.7 Hz, 1H); 5.21 (s, 2H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H);3.79 (s, 3H); 2.24 (s, 3H); 1.31 (s, 9H).

To a solution of the above ester (199 mg, 0.363 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (46 mg, 1.10 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1 h undercooling, acetic acid (0.063 mL; 1.10 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL). The combinedorganic layers were washed with water (2×20 mL) and brine (2×20 mL),dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (2×5 mL) yielding the title acid aswhite solid.

Yield: 134 mg (70%).

M.p.: 144-147° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.68 (m, 1H); 7.59 (m, 1H);7.46 (d, J=8.2 Hz, 2H); 7.31 (d, J=8.5 Hz, 2H); 7.17 (d, J=8.3 Hz, 2H);7.15 (d, J=8.1 Hz, 2H); 6.67 (d, J=2.7 Hz, 1H); 6.65 (d, 1H); 6.53 (dd,J=8.9 and 2.9 Hz, 1H); 6.33 (m, 1H); 6.31 (t, J=6.7 Hz, 1H); 5.21 (s,2H); 4.60 (s, 2H); 4.47 (d, J=6.8 Hz, 2H); 2.24 (s, ˜3H); 1.30 (s, 9H).

Example 53(E)-[4-[3-(4-Cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

To a degassed solution of potassium tert-butoxide (2.08 g, 18.51 mmol)in dry dimethylsulphoxide (6 mL), 4-bromo-benzenethiol (3.5 g, 18.5mmol) was added and the mixture was stirred for 15 min at ambienttemperature under nitrogen. Bromocyclopropane (4.4 mL, 55.5 mmol) wasadded afterwards and the reaction mixture was heated at 80° C. for 24 hin a sealed vessel. The mixture was cooled, diluted with ether (150 mL)and washed with water (100 mL). The aqueous layer was extracted withether (3×50 mL). Combined organic extracts were finally dried withanhydrous magnesium sulfate. 1-Bromo-4-cyclopropyl-sulfanylbenzene wasobtained after evaporation of the solvent as yellow liquid.

Yield: 3.49 g (82%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.70.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.40 (d, J=8.6 Hz, 2H); 7.23(d, J=8.5 Hz, 2H); 2.16 (m, 1H); 1.08 (m, 2H); 0.69 (m, 2H).

To a degassed solution of the above bromide (5.8 g, 25.3 mmol) inanhydrous tetrahydrofuran (33 mL), copper(I) iodide (145 mg, 0.759 mol)and tetrakis(triphenylphosphine)palladium (878 mg, 0.760 mmol) wereadded and the mixture was cooled down with ice bath.1,8-Diazabicyclo[5.4.0]undec-7-ene (5.68 mL, 38.0 mmol) was added andthe reaction mixture was degassed again. A degassed solution ofpropargyl alcohol (2.20 mL, 38.0 mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise afterwards and the reaction mixture was stirredat 50° C. overnight under nitrogen. After cooling the mixture wasdiluted with ether (100 mL) and washed with water (40 mL) and 15%hydrochloric acid (2×40 mL). The aqueous layer was extracted with ether(5×40 mL), the combined organic extracts were washed with 10% sodiumhydrogen carbonate (40 mL) and brine (2×40 mL) and dried with anhydrousmagnesium sulfate. The crude product was purified by columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1)yielding 3-(4-cyclopropylsulfanylphenyl)-prop-2-yn-1-ol as yellow oil,which solidifies in refrigerator.

Yield: 4.45 g (86%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.37 (d, J=8.4 Hz, 2H); 7.31(d, J=8.4 Hz, 2H); 4.51 (d, J=6.1 Hz, 2H); 2.18 (m, 1H); 1.77 (t, J=6.1Hz, 1H); 1.11 (m, 2H); 0.71 (m, 2H).

M Solution of lithium aluminum hydride in tetrahydrofuran (21.8 mL, 21.8mmol) was added to sodium methoxide (55 mg, 1.01 mmol) under nitrogen.The mixture was cooled to 0° C. and a solution of the above hydroxyderivative (4.45 g, 21.8 mmol) in dry tetrahydrofuran (30 mL) was addeddropwise. The reaction mixture was stirred at 0° C. for 3.5 h; dry ethylacetate (6.90 mL, 70.2 mmol) was added and the whole mixture was stirredat ambient temperature for 30 min. A degassed solution of1,4-diiodobenzene (7.26 g, 21.8 mmol) in anhydrous tetrahydrofuran (22mL), anhydrous zinc chloride (1.8 g, 13.3 mmol),tris(dibenzylidene-acetone)dipalladium chloroform complex (0.480 g,0.464 mmol), and tri-(2-furyl)phosphine (0.556 g, 2.39 mmol) were added;the mixture was degassed and stirred at 65° C. for 24 h under nitrogen.The suspension was cooled down; methanol (12 mL) was added and themixture was stirred for additional 1 h. The reaction mixture was dilutedwith ether (100 mL) and saturated aqueous solution of ammonium chloride(7 mL), filtered through a paddle of silica gel and the paddle wasthoroughly washed with ether (80 mL). The solvents were evaporated invacuo and the residue was separated by flash column chromatography(silica gel Fluka 60, dichloromethane/ethyl acetate 20:1) affording(Z)-3-(4-cyclopropylsulfanyl-phenyl)-3-(4-iodophenyl)prop-2-en-1-ol asyellow oil.

Yield: 3.44 g (39%).

R_(F) (SiO₂, dichloromethane/ethyl acetate 20:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.71 (d, J=8.3 Hz, 2H); 7.28(d, J=8.5 Hz, 2H); 7.15 (d, J=8.5 Hz, 2H); 6.92 (d, J=8.3 Hz, 2H); 6.23(t, J=6.9 Hz, 1H); 4.19 (m, 2H); 2.17 (m, 1H); 1.43 (t, J=5.3 Hz, 1H);1.07 (m, 2H); 0.69 (m, 2H).

The above allyl alcohol (3.40 g, 8.30 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (1.79 g, 9.13 mmol; compoundVUFB-21004) and triphenylphosphine (2.5 g, 9.55 mmol) were dissolved ina mixture of anhydrous toluene (38 mL) and tetrahydrofuran (13 mL). Themixture was cooled to 0° C., kept under nitrogen and a degassed solutionof diisopropyl azodicarboxylate (1.88 mL, 9.55 mmol) in anhydroustetrahydrofuran (5 mL) was added dropwise. The reaction mixture wasallowed to warm up to ambient temperature and then was stirredovernight. The solvents were evaporated in vacuo and the residue wassubmitted to flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 10:1-8:1) affording methyl(Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetateas yellowish oil.

Yield: 2.56 g (52%).

R_(F) (SiO₂, hexanes/ethyl acetate 4:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.74 (d, J=8.2 Hz, 2H); 7.30(d, J=8.4 Hz, 2H); 7.17 (d, J=8.3 Hz, 2H); 6.97 (d, J=8.2 Hz, 2H); 6.69(d, J=2.3 Hz, 1H); 6.64 (d, J=8.8 Hz, 1H); 6.59 (dd, J=8.8 and 2.7 Hz,1H); 6.30 (t, J=6.7 Hz, 1H); 4.60 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.81(s, 3H), 2.27 (s, 3H); 2.19 (m, 1H); 1.09 (m, 2H); 0.70 (m, 2H).

To a degassed solution of the above ester (1 g, 1.705 mmol),N-propargylmorpholine (440 mg, 3.515 mmol) and diisopropylamine (1.12mL, 7.96 mmol) in anhydrous tetrahydrofuran (27 mL),bis(triphenylphosphine)palladium(II) dichloride (95 mg, 0.135 mmol) andcopper(I) iodide (27.0 mg, 0.142 mmol) were added. The reaction mixturewas stirred at 50° C. overnight under nitrogen. The solvents wereevaporated in vacuo and the residue was twice purified by flash columnchromatography (silica gel Fluka 60, chloroform/methanol 100:0-95:5 andthen chloroform/ethyl acetate/methanol 80:13:7) yielding methyl(E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas yellow oil.

Yield: 680 mg (68%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.48 (d, J=7.9 Hz, 2H); 7.29(d, J=7.9 Hz, 2H); 7.18 (d, J=8.2 Hz, 4H); 6.69 (d, J=2.6 Hz, 1H); 6.65(d, J=8.8 Hz, 1H); 6.58 (dd, J=8.8 and 2.7 Hz, 1H); 6.30 (t, J=6.7 Hz,1H); 4.60 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 3.80 (m, 7H); 3.56 (s, 2H);2.68 (t, J=4.5 Hz, 4H); 2.26 (s, 3H); 2.20 (m, 1H); 1.09 (m, 2H); 0.71(m, 2H).

The above ester (690 mg, 1.18 mmol) was dissolved in a mixture oftetrahydrofuran (20 mL) and methanol (10 mL) and a solution of lithiumhydroxide monohydrate (112 mg, 2.66 mmol) in distilled water (4 mL) wasadded. The mixture was stirred overnight and then diluted with saturatedaqueous solution of ammonium chloride (112 mL). The resulting mixturewas extracted with ether (3×50 mL); the combined organic layers weredried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes yielding the title acid as whitepowder.

Yield: 440 mg (65%).

M.p.: 78-82° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.1 Hz, 2H); 7.27(d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 4H); 6.68 (d, J=2.7 Hz, 1H); 6.64(d, J=8.8 Hz, 1H); 6.54 (dd, J=8.8 and 2.9 Hz, 1H); 6.30 (t, J=6.8 Hz,1H); 4.59 (s, 2H); 4.48 (d, J=6.8 Hz, 2H); 3.89 (t, J=4.6 Hz, 4H); 3.80(s, 2H); 2.99 (t, J=4.5 Hz, 4H); 2.24 (s, 3H); 2.19 (m, 1H); 1.07 (m,2H); 0.69 (m, 2H).

Example 54(E)-[4-[3-(4-Cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]-allyloxy]2-methylphenoxy]aceticAcid

To a degassed solution of methyl(Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(480 mg, 0.818 mmol; prepared as described in example 53),N,N-dimethylpropargylamine (0.175 mL, 1.64 mmol) and diisopropylamine(0.539 mL, 3.85 mmol) in anhydrous tetrahydrofuran (10 mL),bis(triphenylphosphine)palladium(II) dichloride (29 mg, 0.041 mmol) andcopper(I) iodide (13 mg, 0.068 mmol) were added. The reaction mixturewas stirred at ambient temperature over night under nitrogen.

The solvents were evaporated in vacuo and the residue was purified byflash column chromatography (silica gel Fluka 60,dichloromethane/methanol 99:1-98:2) yielding methyl(E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(N,N-dimethylamino)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate asyellow oil.

Yield: 367 mg (83%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.47 (d, J=8.2 Hz, 2H); 7.28(d, J=8.4 Hz, ˜2H); 7.16 (d, J=8.6 Hz, 2H); 7.15 (d, J=8.2 Hz, 2H); 6.68(d, J=2.8 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.8 Hz,1H); 6.28 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 3.51 (s, 2H); 2.39 (s, 6H); 2.25 (s, 3H); 2.17 (m, 1H); 1.07(m, 2H); 0.69 (m, 2H).

To a solution of the above ester (362 mg, 0.668 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (84 mg, 2.00 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.115 mL; 2.01 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL).

The combined organic layers were washed with water (2×20 mL) and brine(2×20 mL), dried with anhydrous magnesium sulfate and evaporated invacuo. The residue was triturated with hexanes (2×5 mL) yielding thetitle acid as white solid.

Yield: 186 mg (53%).

M.p.: 82-86° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.43 (d, J=8.2 Hz, 2H); 7.28(d, ˜2H); 7.17 (d, J=8.5 Hz, 2H); 7.16 (d, J=8.1 Hz, 2H); 6.69 (d, J=2.7Hz, 1H); 6.61 (d, J=8.8 Hz, 1H); 6.43 (dd, J=8.7 and 2.9 Hz, 1H); 6.34(t, J=6.9 Hz, 1H); 4.52 (s, 2H); 4.39 (d, J=7.0 Hz, 2H); 3.89 (s, 2H);2.67 (s, 6H); 2.25 (s, 3H); 2.17 (m, 1H); 1.07 (m, 2H); 0.69 (m, 2H).

Example 55(E)-[4-[3-(4-Cyclopropylsulfinylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

A solution of(E)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]aceticacid (290 mg, 0.509 mmol; example 53) in acetic acid (8 mL) was cooleddown with crushed ice and 30% aqueous hydrogen peroxide (62 μL, 0611mmol) was added. The mixture was allowed to stand overnight at ambienttemperature. The mixture was diluted with water (20 mL) and extractedwith ethyl acetate (3×20 mL). The combined organic layers were driedwith anhydrous magnesium sulfate and evaporated in vacuo. The crudeproduct was purified by column chromatography (silica gel Fluka 60,chloroform/methanol 80:20) affording the title acid as yellowish powder.

Yield: 160 mg (54%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.62 (d, J=8.3 Hz, 2H); 7.48(d, J=8.1 Hz, 2H); 7.39 (d, J=8.4 Hz, 2H); 7.15 (d, J=8.1 Hz, 2H); 6.68(d, J=2.8 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H); 6.54 (dd, J=8.9 and 2.9 Hz,1H); 6.39 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.52 (d, J=6.7 Hz, 2H); 3.87(t, J=4.4 Hz, 4H); 3.77 (s, 2H); 2.96 (t, J=4.5 Hz, 4H); 2.35 (m, 1H);2.24 (s, 3H); 1.06-0.85 (m, 4H).

Example 56(E)-[2-Methyl-4-[[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]allyloxy]phenoxy]aceticAcid

To a degassed solution of 1-bromo-4-(trifluoromethylsulfanyl)benzene(4.8 g, 18.7 mmol) in tetrahydrofuran (40 mL) was added in the followingorder: copper(I) iodide (106 mg, 0.56 mmol),tetrakis(triphenylphosphine)palladium (647 mg, 0.56 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (3.36 mL, 22.3 mmol). The resultingmixture was degassed one more time and a solution of propargyl alcohol(1.30 mL, 22.3 mmol) in tetrahydrofuran (5 mL) was added over period of10 min. The reaction mixture was slowly heated up to 50° C. and thenstirred at this temperature for 6 h and then left to stand at ambienttemperature over night. The mixture was diluted with ether (50 mL) andacidified with 5% hydrochloric acid to pH 2. Ethereal solution waswashed with water (2×15 mL), saturated solution of sodium hydrogencarbonate (15 mL) and brine (15 mL), dried with anhydrous magnesiumsulfate and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 85:15)affording 3-[4-(trifluoromethylsulfanyl)phenyl]prop-2-yn-1-ol.

Yield: 3.85 g (90%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.60 (d, J=8.5 Hz, 2H); 7.47(d, J=8.5 Hz, 2H); 4.52 (d, J=6.1 Hz, 2H); 1.84 (t, J=6.2 Hz, 1H).

Sodium methoxide (44 mg, 0.8 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (16.0 mL, 16.0 mmol) under argon.The mixture was cooled to 0° C. and a solution of the above hydroxyderivative (3.78 g, 16.3 mmol) in tetrahydrofuran (50 mL) was added over30 min. The reaction was stirred at 0° C. for 3 h; dry ethyl acetate(4.9 mL, 50 mmol) was added and the whole mixture was stirred at ambienttemperature for 10 min. A degassed solution of 1,4-diiodobenzene (6.44g, 19.5 mmol) in dry tetrahydrofuran (10 mL), anhydrous zinc chloride(1.33 g, 9.76 mmol), tris(dibenzylideneacetone)dipalladium chloroformcomplex (0.33 g, 0.325 mmol), and tri-2-furylphosphine (0.416 g, 1.78mmol) were added; the mixture was degassed and then heated at 50-60° C.for 24 h under argon. The suspension was cooled down; methanol (8 mL)was added and the mixture was stirred for additional 1 h. The reactionmixture was diluted with ether (200 mL) and saturated aqueous solutionof ammonium chloride (4.5 mL) was added. The suspension was filteredthrough a paddle of silica gel and the paddle was thoroughly washed withether (50 mL). The filtrate was evaporated in vacuo and the residue wasseparated by flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 9:1) affording(Z)-3-(4-iodo-phenyl)-3-[4-(trifluoromethylsulfanyl)phenyl]prop-2-en-1-ol.

Yield: 1.04 g (15%).

R_(F) (SiO₂, chloroform): 0.15.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.74-7.04 (m, 8H); 6.31 (t,J=6.8 Hz, 1H); 4.22 (d, J=7.0 Hz, 2H); 2.36 (s, 1H).

The above allyl alcohol (1.09 g, 2.4 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.549 g, 27.9 mmol; example 2) andtriphenylphosphine (0.755 g, 28.8 mmol) were dissolved in a mixture ofanhydrous toluene (20 mL) and tetrahydrofuran (10 mL). The mixture wascooled to 0° C., kept under argon and a degassed solution of diisopropylazodicarboxylate (0.56 mL, 28.8 mmol) in anhydrous tetrahydrofuran (5mL) was added dropwise during 30 min. The reaction mixture was allowedto warm up the ambient temperature with the bath and then was stirredfor 5 h. The solvents were evaporated in vacuo and the residue wassubmitted to flash column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 10:1) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methyl-phenoxy]acetateas solid mass.

Yield: 0.70 g (73%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.75 (d, J=8.3 Hz, 2H); 7.57(d, J=8.3 Hz, 2H); 7.28 (d, J=8.3 Hz, 2H); 6.94 (d, J=8.3 Hz, 2H);6.68-6.56 (m, 3H); 6.37 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.49 (d, J=6.6Hz, 2H); 3.79 (s, 3H); 2.25 (s, 3H).

N-Propargylmorpholine (146 mg, 1.17 mmol) was added to a solution of theabove iodo derivative (360 mg, 0.586 mmol) and diisopropylamine (0.38mL, 2.7 mmol) in tetrahydrofuran (9 mL). The mixture was degassed andcopper(I) iodide (8.9 mg, 0.046 mmol) andbis(triphenylphosphine)palladium(II) dichloride (20.5 mg, 0.029 mmol)were added. The reaction mixture was stirred under argon at ambienttemperature for 20 h, filtered and the filtrate was evaporated in vacuo.The residue was purified by flash column chromatography (silica gelFluka 60, chloroform/methanol 99:1) yielding(E)-[2-methyl-4-[[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]allyloxy]phenoxy]acetate.

Yield: 204 mg (57%).

R_(F) (SiO₂, chloroform/methanol 19:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.58 (d, J=8.3 Hz, 2H); 7.49(d, J=8.3 Hz, 2H); 7.30 (d, J=8.3 Hz, 2H); 7.16 (d, J=8.3 Hz, 2H);6.69-6.56 (m, 3H); 6.38 (t, J=6.7 Hz, 1H); 4.60 (s, 2H); 4.53 (d, J=6.7Hz, 2H); 3.80 (s, 3H); 3.78 (m, 4H); 3.55 (s, 2H); 2.68 (m, 4H); 2.27(s, 3H).

To a solution of the above ester (184 mg, 0.30 mmol) intetrahydrofuran/methanol mixture (5:1, 11 mL), a solution of lithiumhydroxide monohydrate (25.2 mg, 0.60 mmol) in distilled water (1 mL) wasadded. The solution was stirred for 2 h at ambient temperature, aceticacid (34.3 μL; 0.60 mmol) was added and the mixture was diluted withethyl acetate (20 mL). The solution was washed with water (2×10 mL),dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (3×15 mL) yielding the title acid astan solid.

Yield: 132 mg (74%).

M.p.: 71-80° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.56 (d, 2H); 7.45 (d, 2H);7.27 (d, J=8.2 Hz, 2H); 7.11 (d, J=8.2 Hz, 2H); 6.63 (m, 2H); 6.47 (m,1H); 6.38 (t, J=6.7 Hz, 1H); 4.54 (s, 2H); 4.47 (d, J=6.7 Hz, 2H); 3.84(m, 4H); 3.76 (s, 2H); 2.95 (m, 4H); 2.24 (s, 3H).

Example 57(E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)-phenyl]allyloxy]-2-methylphenoxy]aceticAcid

1-Propargylpiperidin-4-ol (154 mg, 1.10 mmol) was added to a solution ofmethyl(Z)-[4-[3-(4-iodophenyl)-3-[4-(trifluoromethyl-sulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetate(340 mg, 0.553 mmol; prepared as described in example 56) anddiisopropylamine (0.35 mL, 2.49 mmol) in tetrahydrofuran (9 mL). Themixture was degassed and copper(I) iodide (8.4 mg, 0.044 mmol) andbis(triphenylphosphine)palladium(II) dichloride (19.3 mg, 0.027 mmol)were added. The reaction mixture was stirred under argon at ambienttemperature for 20 h, filtered and the filtrate was evaporated in vacuo.The residue was purified by flash column chromatography (silica gelFluka 60, chloroform/methanol 97:3) yielding methyl(E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(trifluoromethylsulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 243 mg (70%).

R_(F) (SiO₂, chloroform/methanol 19:3): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.57 (d, J=8.1 Hz, 2H); 7.50(d, J=8.1 Hz, 2H); 7.27 (d, J=8.1 Hz, 2H); 7.16 (d, J=8.1 Hz, 2H);6.67-6.61 (m, 2H); 6.53-6.50 (m, 1H); 6.40 (t, J=6.7 Hz, 1H); 4.57 (s,2H); 4.48 (d, J=6.7 Hz, 2H); 4.17 (s, 2H); 4.05 (m, 1H); 3.52 (m, 2H);3.31 (m, 2H); 2.23 (s, 3H); 2.22 (m, 2H); 2.02 (m, 2H).

To a solution of the above ester (224 mg, 0.357 mmol) intetrahydrofuran/methanol mixture (5:1, 11 mL), a solution of lithiumhydroxide monohydrate (30.0 mg, 0.715 mmol) in distilled water (1 mL)was added. The solution was stirred for 2 h at ambient temperature,acetic acid (40.8 μL; 0.715 mmol) was added and the mixture was dilutedwith ethyl acetate (20 mL). The solution was washed with water (2×10mL), dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (3×15 mL) yielding the title acid astan solid.

Yield: 159 mg (73%).

M.p.: 87-96° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.10.

¹H NMR spectrum (300 MHz, CDCl3+AcOH-d₄, δ_(H)): 7.58 (d, 2H); 7.50 (d,2H); 7.28 (d, J=8.2 Hz, 2H); 7.16 (d, J=8.2 Hz, 2H); 6.66 (m, 2H); 6.51(m, 1H); 6.41 (t, J=6.7 Hz, 1H); 4.57 (s, 2H); 4.47 (d, J=6.7 Hz, 2H);4.17 (s, 2H); 4.05 (m, 1H); 3.53 (m, 2H); 3.31 (m, 2H); 2.23 (m, 2H);2.23 (s, 3H); 2.02 (m, 2H).

Example 58(E)-[4-[3-[4-(Methylsulfinyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

30% Aqueous hydrogen peroxide (0.0618 mL, 0.6 mmol) was added to asolution of(E)-[4-[3-[4-(methylsulfanyl)phenyl]-3-[4-[3-(pyrazol-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticacid (262 mg, 0.5 mmol; example 48) in glacial acetic acid (7 mL) at 5°C. under stirring. The mixture was left to stand over night at ambienttemperature, diluted with water (40 mL) and extracted with ethyl acetate(2×20 mL). The combined extracts were alkalized with 15% aqueoussolution of ammonium hydroxide; the solution was washed with water (10mL) and brine (10 mL), dried with anhydrous magnesium sulphate andevaporated in vacuo. The residue was triturated with hexanes (3×15 mL)to yield the title compound as pale solid.

Yield: 121 mg (45%).

M.p.: 139-145° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.68 (d, J=2.2 Hz, 1H);7.59-7.36 (m, 7H); 7.14 (d, J=8.2 Hz, 2H); 6.64 (m, 2H); 6.55 (m, 1H);6.37 (t, J=6.6 Hz, 1H); 6.33 (t, J=2.1 Hz, 1H); 5.22 (s, 2H); 4.57 (s,2H); 4.50 (d, J=6.6 Hz, 2H); 2.76 (s, 3H); 2.24 (s, 3H).

Example 59(E)-[4-[3-[4-[3-(4-Hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(methylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]aceticAcid

1-Propargylpiperidin-4-ol (0.401 g, 2.88 mmol) and diisopropylamine (1.6mL, 11.73 mmol) were added to a solution of methyl(Z)-[4-[3-(4-iodophenyl)-3-[4-(methylsulfanyl)phenyl]allyloxy]-2-methylphenoxy]acetate(1.40 g, 2.5 mmol; prepared as described in example 40) intetrahydrofuran (12 mL) and triethylamine (12 mL). The mixture wasdegassed and copper(I) iodide (49.0 mg, 0.256 mmol) andtetrakis(triphenylphosphine)palladium (148 g, 0.128 mmol) were added.The reaction mixture was stirred at ambient temperature for 20 h andevaporated in vacuo. The residue was purified by flash columnchromatography (silica gel Fluka 60, chloroform/methanol 97:3) yieldingmethyl(E)-[4-[3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]-3-[4-(methylsulfanyl)phenyl]-allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 800 mg (88%).

R_(F) (SiO₂, chloroform/methanol 9:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.3 Hz, 2H); 7.16(s, 4H); 7.14 (d, J=8.3 Hz, 2H); 6.67-6.54 (m, 3H); 6.27 (t, J=6.7 Hz,1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.74 (m, 1H);3.56 (s, 2H); 2.88 (m, 2H); 2.47 (s, 3H); 2.44 (m, 2H); 2.24 (s, 3H);1.95 (m, 2H); 1.67 (m, 2H).

To a solution of the above ester (800 mg, 1.41 mmol) in ethanol (15 mL),a 4.4 M solution of sodium hydroxide (0.64 mL, 2.82 mmol) was added. Themixture was stirred for 2 h at ambient temperature and then acetic acid(0.166 mL) and chloroform (100 mL) were added. The solid mass wasfiltered off, washed with chloroform (20 mL) and water (2×20 mL) anddried in vacuo. This afforded the title acid as white solid.

Yield: 482 mg (62%).

M.p.: 160-162° C.

R_(F) (SiO₂, chloroform/methanol 7:3): 0.15.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.56 (d, J=8.2 Hz, 2H); 7.24(d, J=8.2 Hz, 2H); 7.17 (s, 4H); 6.69 (m, 2H); 6.58 (dd, J=8.9 and 2.8Hz, 1H); 6.36 (t, J=6.7 Hz, 1H); 4.65 (s, 2H); 4.50 (d, J=6.7 Hz, 2H);4.29 (s, 2H); 3.56 (bs, ˜1H); 2.45 (s, 3H); 2.22 (m, ˜4H); 2.20 (s, 3H);2.05 (m, ˜4H).

Example 60(Z)-[4-[3-(4-tert-Butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticacid

1-Ethynyl-4-(hydroxymethyl)benzene (169 mg, 1.28 mmol) anddiisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(364 mg, 0.638 mmol; prepared as described in example 30) intetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide(10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride(22 mg, 0.031 mmol) were added. The reaction mixture was stirred atambient temperature overnight, filtered and the filtrate was evaporatedin vacuo. The residue was purified by flash column chromatography(silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl(Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas brown oil.

Yield: 335 mg (92%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.60.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.56 (d, J=8.3 Hz, ˜2H); 7.55(d, J=8.2 Hz, ˜2H); 7.37 (d, J=8.2 Hz, ˜2H); 7.32 (d, J=8.5 Hz, ˜2H);7.21 (d, J=8.2 Hz, ˜2H); 7.19 (d, J=8.4 Hz, ˜2H); 6.68 (d, J=2.7 Hz,1H); 6.63 (d, J=8.7 Hz, 1H); 6.57 (dd, J=8.9 and 2.8 Hz, 1H); 6.30 (t,J=6.6 Hz, 1H); 4.72 (m, ˜2H); 4.58 (s, 2H); 4.51 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 2.25 (s, 3H); 1.31 (s, 9H).

To a solution of the above ester (335 mg, 0.583 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (74 mg, 1.76 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 0.5 h undercooling, acetic acid (0.101 mL; 1.76 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL). The combinedorganic layers were washed with water (2×20 mL) and brine (2×20 mL). Theorganic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. This afforded the title acid as brown solid.

Yield: 186 mg (57%).

M.p.: 62-73° C.

R_(F) (SiO₂, ethyl acetate/methanol 1:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.58 (d, J=8.3 Hz, 2H); 7.57(d, J=8.2 Hz, 2H); 7.39 (d, J=8.3 Hz, 2H); 7.34 (d, J=8.5 Hz, 2H); 7.23(d, J=8.2 Hz, 2H); 7.22 (d, J=8.5 Hz, 2H); 6.71 (d, J=2.9 Hz, 1H); 6.68(d, 1H); 6.61 (dd, J=8.8 and 2.8 Hz, 1H); 6.32 (t, J=6.6 Hz, 1H); 4.75(s, 2H); 4.62 (s, 2H); 4.54 (d, J=6.7 Hz, 2H); 2.26 (s, 3H); 1.33 (s,˜9H).

Example 61(E)-[4-[3-(4-Bromophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Under nitrogen atmosphere, N-propargylmorpholine (190 mg, 1.52 mmol) anddiisopropylamine (360 mg, 3.56 mmol) were added to a degassed solutionof methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]acetate(445 mg, 0.75 mmol) in tetrahydrofuran (15 mL).Bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) andcopper(I) iodide (15 mg, 0.078 mmol) were added; the reaction mixturewas degassed again and then stirred at ambient temperature over nightunder inert atmosphere. The reaction mixture was filtered through apaddle of silica gel; the paddle was washed with ethyl acetate (4×15 mL)and the combined organic filtrates were evaporated in vacuo. The residuewas purified by column chromatography (silica gel Fluka 60,dichloromethane/methanol 98:2) yielding(E)-[4-[3-(4-bromophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate.

Yield: 350 mg (79%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.41(d, J=8.6 Hz, 2H); 7.14-7.09 (m, 4H); 6.67 (d, J=2.8 Hz, 1H); 6.62 (d,J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.8 Hz, 1H); 6.29 (t, J=6.7 Hz, 1H);4.58 (s, 2H); 4.49 (d, J=6.6 Hz, 2H); 3.79-3.78 (m, 7H); 3.54 (s, 2H);2.68-2.65 (m, 3H), 2.25 (s, 3H).

A solution of the above ester (0.35 g, 0.59 mmol) in a mixture oftetrahydrofuran (5 mL) and methanol (2 mL) was cooled to 0° C. Asolution of lithium hydroxide monohydrate (60 mg, 1.22 mmol) indistilled water (2.5 mL) was added and the mixture was stirred for 2 h.The reaction mixture was acidified with 2 M HCl to pH-6 and then dilutedwith 10% aqueous solution of ammonium chloride (20 mL) and ethyl acetate(20 mL). The phases were separated, the aqueous phase was washed withethyl acetate (4×15 mL); the combined organic extracts were washed with10% aqueous solution of ammonium chloride (2×15 mL) and brine (2×15 mL),dried with anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was purified using flash column chromatography (silica gel Fluka60, dichloromethane/methanol/acetic acid 95:5:1) affording oil which wastriturated with hexanes (2×7 mL) yielding the title compound asamorphous white solid.

Yield: 0.210 g (67%).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.15.

M.p.: 132-149° C.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.53-7.48 (m, 4H); 7.19-7.13(m, 4H); 6.68-6.58 (m, 3H); 6.34 (t, J=6.1 Hz, 1H); 4.55 (s, 2H); 4.45(d, J=6.1 Hz, 2H); 3.60 (bs, 4H); 3.52 (s, 2H); ˜2.50 (m, overlapped);2.12 (s, 3H).

Example 62(E)-[4-[3-(4-Bromophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Under nitrogen atmosphere, 4-hydroxy-1-propargylpiperidine (210 mg, 1.50mmol) and diisopropylamine (360 mg, 3.56 mmol) were added to a degassedsolution of methyl(Z)[4-[3-(4-iodoophenyl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]acetate(445 mg, 0.75 mmol) in tetrahydrofuran (15 mL).Bis(triphenylphosphine)palladium(II) dichloride (30 mg, 0.042 mmol) andcopper(I) iodide (15 mg, 0.078 mmol) were added; the reaction mixturewas degassed again and stirred at ambient temperature overnight underinert atmosphere. The reaction mixture was filtered through a paddle ofsilica gel; the paddle was washed with ethyl acetate (4×15 mL) and thecombined organic filtrates were evaporated in vacuo. The residue waspurified using column chromatography (silica gel Fluka 60,dichloromethane/methanol 95:5) yielding(E)-[4-[3-(4-bromophenyl)-3-[4-[3-(4-hydroxypiperidin-1-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 110 mg (24%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.2 Hz, 2H); 7.42(d, J=8.5 Hz, 2H); 7.14-7.09 (m, 4H); 6.67 (d, J=2.7 Hz, 1H); 6.62 (d,J=8.8 Hz, 1H); 6.56 (dd, J=8.9 and 2.9 Hz, 1H); 6.29 (t, J=6.7 Hz, 1H);4.58 (s, 2H); 4.49 (d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.55 (s, 2H);2.93-2.88 (m, 2H); 2.49-2.42 (m, 2H); 2.25 (s, 3H); 1.97-1.95 (m, 2H);1.73-1.62 (m, 3H).

A solution of the above ester (0.11 g, 0.18 mmol) in a mixture oftetrahydrofuran (5 mL) and methanol (2 mL) was cooled to 0° C. Asolution of lithium hydroxide monohydrate (20 mg, 0.40 mmol) indistilled water (1.5 mL) was added and the mixture was stirred for 2 h.The reaction mixture was acidified with 2 M HCl to pH-6 and then dilutedwith 10% aqueous solution of ammonium chloride (15 mL) and ethyl acetate(15 mL). Phases were separated and the aqueous phase was washed withethyl acetate (4×15 mL). The combined organic extracts were washed with10% aqueous solution of ammonium chloride (2×15 mL) and brine (2×15 mL),dried with anhydrous magnesium sulfate and concentrated in vacuo. Theresidue was triturated with hexanes (2×5 mL) yielding the title compoundas amorphous grayish solid.

Yield: 0.050 g (46%).

R_(F) (SiO₂, chloroform/methanol 85:15): 0.20.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.53-7.47 (m, 4H); 7.18-7.13(m, 4H); 6.70-6.67 (m, 2H); 6.59 (dd, J=8.6 and 2.5 Hz, 1H); 6.34 (t,J=6.6 Hz, 1H); 4.55 (s, 2H); 4.45 (d, J=6.6 Hz, 2H); 3.62-3.59 (m, 4H);3.52 (s, 2H); 2.12 (s, 3H); 1.88-1.86 (m, 5H).

Example 63(E)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionicAcid

A mixture of 4-hydroxy-2-methylacetophenone (13.8 g, 91.8 mmol), benzylchloride (12.7 g, 100 mmol), potassium carbonate (13.8 g, 100 ml) and2-butanone (100 mL) was refluxed under stirring for 10 h, filtered andevaporated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, benzene) affording4-benzyloxy-2-methylacetophenone.

Yield 16.7 g (76%).

R_(F) (SiO₂, chloroform): 0.40.

M.p.: 51-53° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.74 (d, J=8.7 Hz, 2H); 7.39(m, 5H); 6.81 (m, 2H); 5.09 (s, 2H); 2.56 (s, 3H); 2.53 (s, 3H).

Diethyl carbonate (19.5 g, 165 mmol) was dissolved in ether (100 mL) and50% suspension of sodium hydride in oil (8.0 g, 167 mmol) was carefullyadded. A solution of the above acetophenone (16.7 g, 69.3 mmol) inbenzene (100 mL) was added and the mixture was refluxed for 5 h. Aftercooling, the mixture was poured on ice with concentrated hydrochloricacid (50 mL); the organic layer was separated, dried with anhydrouspotassium carbonate and evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, benzene/chloroform 1:1)affording ethyl 4-benzyloxy-2-methylbenzoylacetate.

Yield: 16.1 g (74%).

M.p.: 59-60° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.69 (d, J=8.4 Hz, 2H); 7.39(m, 5H); 6.82 (m, 2H); 5.10 (s, 2H); 4.19 (q, J=7.1 Hz, 2H); 3.91 (s,2H); 2.57 (s, 3H); 1.24 (t, J=7.1 Hz, 3H).

5% Palladium on carbon (4.0 g) was added to a solution of the aboveketo-ester (10.4 g, 33.3 mmol) in ethyl acetate (300 mL) and the mixturewas hydrogenated at atmospheric pressure and ambient temperature for 5h. After filtration of the catalyst, the solvent was evaporated in vacuoand the residue was purified by column chromatography on silica gel(Fluka 60, chloroform/ethyl acetate 1:1) affording ethyl3-(4-hydroxy-2-methylphenyl)propionate.

Yield 6.15 g (89%).

R_(F) (SiO₂, chloroform): 0.10.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 6.97 (d, J=8.1 Hz, 1H); 6.64(d, J=2.5 Hz, 1H); 6.60 (dd, J=2.5 and 8.1 Hz, 1H); 4.14 (q, J=7.1 Hz,2H); 2.86 (t, J=8.4 Hz, 2H); 2.54 (t, J=8.4 Hz, 3H); 2.25 (s, 3H); 1.25(t, J=7.1 Hz, 3H).

The above ester (0.60 g, 2.88 mmol),(Z)-[3-(4-chlorophenyl)-3-(4-iodophenyl)]allyl alcohol (0.78 g, 2.2mmol, prepared as described in example 7) and triphenylphosphine (0.80g, 3.05 mmol) were dissolved in a mixture of anhydrous toluene (10 mL)and tetrahydrofuran (8 mL). The mixture was cooled to 0° C., kept undernitrogen and diisopropyl azodicarboxylate (0.70 g, 3.28 mmol) was addeddropwise. The reaction mixture was stirred at 0° C. for 3 h and then atambient temperature for 24 h. The solvents were evaporated in vacuo andthe residue was submitted to column chromatography (silica gel Fluka 60,benzene) affording ethyl(Z)-[4-[3-(4-chlorophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenyl]propionateas solid mass.

Yield: 0.85 g (69%).

R_(F) (SiO₂, benzene): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.3 Hz, 2H); 7.25(d, J=8.7 Hz, 2H); 7.17 (d, J=8.7 Hz, 2H); 7.01 (d, J=8.3 Hz, 1H); 6.94(d, J=8.3 Hz, 2H); 6.64 (d, J=2.4 Hz, 1H); 6.60 (dd, J=8.3 and 2.4 Hz,1H); 6.30 (t, J=6.7 Hz, 1H); 4.50 (d, J=6.7 Hz, 2H); 4.13 (q, J=7.1 Hz,2H); 2.86 (t, J=8.4 Hz, 2H); 2.52 (t, J=8.4 Hz, 2H); 2.27 (s, 3H); 1.24(t, J=7.1 Hz, 3H).

4-Propargylmorpholine (400 mg, 3.2 mmol) was added under nitrogenatmosphere to a degassed solution of the above ester (410 mg, 0.78 mmol)in a mixture of tetrahydrofuran (10 mL) and triethylamine (8 mL). Thesolution was cooled to 0° C., tetrakis(triphenylphosphine)palladium (90mg, 0.078 mmol) and copper(I) iodide (22 mg, 0.115 mmol) were added. Thereaction mixture was stirred at ambient temperature for 72 h, dilutedwith benzene (100 mL), decanted and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, benzene/ethylacetate 10:0-4:6) yielding ethyl(E)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionateYield: 350 mg (86%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.65.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.3 Hz, 2H); 7.26(d, J=8.4 Hz, 2H); 7.16 (m, 4H); 7.01 (d, J=8.3 Hz, 1H); 6.63 (d, J=2.5Hz, 1H); 6.59 (dd, J=8.3 and 2.5 Hz, 1H); 6.29 (t, J=6.6 Hz, 1H); 4.52(d, J=6.6 Hz, 2H); 4.13 (q, J=7.1 Hz, 2H); 3.78 (m, 4H); 3.53 (s, 2H);2.86 (t, J=7.4 Hz, 2H); 2.66 (m, 4H); 2.52 (t, J=7.4 Hz, 2H) 2.27 (s,3H); 1.24 (t, J=7.1, 3H).

The above ester (0.35 g, 0.627 mmol) was dissolved in ethanol (30 mL), asolution of lithium hydroxide monohydrate (0.10 g, 2.38 mmol) in water(4 mL) was added and the mixture was left to stand for 24 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL), acidified with acetic acid (0.25 mL) and extracted withchloroform (2×50 mL). The organic solution was dried with anhydrouspotassium carbonate and subsequently evaporated in vacuo. The residuewas triturated with hexanes yielding the title compound as amorphoussolid.

Yield: 0.26 g (78%).

R_(F) (SiO₂, chloroform/ethanol/ammonia 1:1:0.05): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.1 Hz, 2H); 7.25(d, J=6.0 Hz, 2H); 7.15 (t, 4H); 7.02 (d, J=8.1 Hz, 1H); 6.63 (d, J=2.5Hz, 1H); 6.59 (dd, J=8.1 and 2.5 Hz, 1H); 6.30 (t, J=6.6 Hz, 1H); 4.51(d, J=6.6 Hz, 2H); 3.79 (bs, 4H); 3.57 (s, 2H); 2.87 (t, J=7.7 Hz, 2H);2.72 (bs, 4H); 2.57 (t, J=7.7 Hz, 2H) 2.26 (s, 3H).

Example 64{4-[(Z)-3-(4-Fluoro-phenyl)-3-(4-phenylethynyl-phenyl)-allyloxy]-2-methyl-phenoxy}-aceticAcid

To a solution of sodium (0.42 g, 18.4 mmol) in ethanol (200 ml) wasadded triethyl phosphonoacetate (4.12 g, 18.4 mmol) and the reactionmixture was stirred for 5 min. To the mixture was added(4-fluoro-phenyl)-(4-phenylethynyl-phenyl)-methanone (3.94 g, 13.12mmol) and refluxed for 48 hours. The cooled reaction mixture wasevaporated in vacuo and purified by preperativ HPLC methode yieldingboth isomers. (E)-3-(4-Fluoro-phenyl)-3-(4-phenylethynyl-phenyl)-acrylicacid ethyl ester was isolated as an oil in 308 mg (6.3%) yield.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.60-6.95 (m, 13H); 6.30 (s,1H); 4.10 (q, J=7.2 Hz, 2H); 1.16 (t, J=7.1 Hz, 3H).

(Z)-3-(4-Fluoro-phenyl)-3-(4-phenylethynyl-phenyl)-acrylic acid ethylester was isolated as solid in 323 mg (6.7%) yield.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55-7.05 (m, 13H); 6.40 (s,1H); 4.05 (q, J=7.2 Hz, 2H); 1.15 (t, J=7.1 Hz, 3H).

A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (4 mL, 4mmol) was added dropwise to a cooled (0° C.) solution of the above(Z)-ester (0.323 g; 0.87 mmol) in dry tetrahydrofuran (40 mL). Thereaction was stirred at the temperature for 4 hr. Then saturatedammoniumchloride (30 ml) after 30 min DCM (150 ml) and hyflo super cellmedium (15 g) were addad to the mixture, which was stirred at ambienttemperature overnight. The mixture was filtered and subsequentlyevaporated in vacuo. The crude product were taken up in DCM (150 ml) andwashed with water (2×50 ml), dried with anhydrous magnesium sulfate andsubsequently evaporated in vacuo. The residue was purified by ISCOcombiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving(Z)-3-(4-fluoro-phenyl)-3-(4-phenylethynylphenyl)-prop-2-en-1-ol.

Yield: 100 mg (34%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55-7.05 (m, 13H); 6.29 (t,J=6.78 Hz, 1H); 4.12 (d, J=6.78 Hz, 2H).

To a solution of the above alcohol (100 mg, 0.305 mmol) in drytetrahydrofuran (20 ml), was added tributylphosphine (0.11 ml, 0.61mmol). The mixture was cooled to 0° C. and added1,1′-(azodicarbonyl)dipiperidine (153 mg, 0.61 mmol), and after 10 min.(4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (65 mg, 0.34 mmol)were added. The reaction mixture was stirred for 1.5 hours at 0° C. andthen allowed to warm up to ambient temperature overnight. To thereaction mixture was added silica gel Fluka 60 (10 g) and the reactionmixture was evaporated in vacuo. The residue was purified by ISCOcombiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving{4-[(Z)-3-(4-fluoro-phenyl)-3-(4-phenylethynyl-phenyl)-allyloxy]-2-methyl-phenoxy}-aceticacid methyl ester as an oil.

Yield: 102 mg (66%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.58-7.15 (m, 13H); 6.70-6.55(m, 3H); 6.35 (t, J=6.78 Hz, 1H); 4.58 (s, 2H); 4.50 (d, J=6.78 Hz, 2H);3.79 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (102 mg, 0.201 mmol) in dioxane (100ml) was added 1N NaOH (1.6 ml, 1.6 mmol) and the reaction mixture wasstirred for 48 hours, evaporated in vacuo and added water (10 ml) andDCM (50 ml) and 1N HCl (3 ml). The DCM phase were dried with anhydrousmagnesium sulfate and subsequently evaporated in vacuo yielding thetitle compound as light yellow solid.

Yield: 96 mg (97%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.55-7.05 (m, 13H); 6.70-6.55(m, 3H); 6.35 (t, J=6.78 Hz, 1H); 4.61 (s, 2H); 4.51 (d, J=6.78 Hz, 2H);2.25 (s, 3H).

Example 65(4-{(E)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)aceticAcid

A solution of (E)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester(0.728 g, 2.2 mmol), dimethyl-prop-2-ynyl-amine (0.56 ml, 6.58 mmol),bis(triphenylphosphine) palladium(II) chloride (0.061 g, 0.088 mmol),copper(I) iodide (1.25 mg, 0.0065 mmol) in dry triethylamine (7 ml) wereheated to 100° C. by microwave irradiation for 20 min. To the cooledreaction mixture was added dichloromethane (20 ml) and silica gel Fluka60 (5 g) and the reaction mixture was evaporated in vacuo. The residuewas purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate85:15) giving(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acidethyl ester as an oil.

Yield: 640 mg (87%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.15 (m, 9H); 6.36 (s,1H); 4.04 (q, J=7.16 Hz, 2H); 3.48 (s, 2H); 2.37 (s, 6H); 1.11 (t,J=7.16 Hz, 3H).

A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (6 ml)was added drop wise to a cooled (0° C.) solution of the above ester(0.600 g; 1.80 mmol) in dry tetrahydrofuran (50 ml). The reactionstirred at the temperature for 4 hours and then added saturatedammoniumchloride (30 ml). After stirring 30 min dichloromethane (150 ml)and hyflo super cell medium (15 g) were added. The mixture was stirredat ambient temperature 2 hours, filtered and evaporated in vacuo. Thecrude product was taken up in dichloromethane (150 ml) and washed withwater (2×50 ml), dried with anhydrous magnesium sulfate and subsequentlyevaporated in vacuo giving(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-prop-2-en-1-ol.

Yield: 430 mg (81%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.30 (m, 5H); 7.20-7.10(m, 4H); 6.30 (t, J=6.78 Hz, 1H); 4.20 (d, J=6.78 Hz, 2H); 3.45 (s, 2H);2.20 (s, 6H).

To a solution of the above alcohol (407 mg, 1.397 mmol) in drytetrahydrofuran (40 mL) was added tributylphosphine (0.50 ml, 2.79mmol). To the mixture was cooled to 0° C. and added1,1′-(azodicarbonyl)dipiperidine (703 mg, 2.79 mmol) and after 10 min.(4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (301 mg, 1.536mmol) was added. After stirring for 1.5 hr at 0° C. the mixture wasallowed to warm up to ambient temperature and stirred overnight. Thereaction mixture was added silica gel Fluka 60 (10 g) and evaporated invacuo. The residue was purified by ISCO combiflash 16 (silica gel,hexane/ethyl acetate 85:15) giving(4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methylphenoxy)-aceticacid methyl ester as an oil.

Yield: 347 mg (53%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.30 (m, 5H); 7.15 (br d,4H); 6.70-6.55 (m, 3H); 6.30 (t, 1H); 4.55-4.45 (m, 4H); 3.70 (s, 2H);3.50 (s, 3H); 2.40 (s, 6H); 2.25 (s, 3H).

To a solution of the above ester (164 mg, 0.349 mmol) in ethanol (40 ml)was added 1N NaOH (1.25 ml) and the reaction mixture was stirred for 3hours. The mixture was evaporated in vacuo and the resulting residue wasdissolved in dichloromethane (50 mL) and extracted with water (10 ml).The aqueous phase was neutralized with 1N HCl (1 ml) and extracted withethyl acetate (20 ml). The ethyl acetate phase was dried with anhydrousmagnesium sulfate and subsequently evaporated in vacuo yielding thetitle acid as light yellow solid.

Yield: 72 mg (45%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.40-7.30 (m, 5H); 7.15 (br d,4H); 6.60 (m, 2H); 6.35 (d, 1H); 6.25 (t, 1H); 4.55-4.45 (m, 4H); 3.70(s, 2H); 2.55 (s, 6H); 2.20 (s, 3H).

Example 66(4-{(Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)aceticAcid

A solution of (Z)-3-(4-bromo-phenyl)-3-phenyl-acrylic acid ethyl ester(1.200 g, 3.6 mmol), dimethyl-prop-2-ynyl-amine (0.9 ml, 10.88 mmol),bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.144 mmol),copper(I) iodide (2.06 mg, 0.0108 mmol) in dry triethylamine (10 ml)were heated to 100° C. by microwave irradiation for 20 min. The cooledreaction mixture was added dichloromethane (20 ml) and silica gel Fluka60 (10 g) and evaporated in vacuo. The resulting residue was purified byISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving(Z)-3-[4-(3-Dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-acrylic acidethyl ester as an oil.

Yield: 6488 mg (54%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.15 (m, 9H); 6.34 (s,1H); 4.10 (q, J=7.16 Hz, 2H); 3.50 (s, 2H); 2.40 (s, 6H); 1.11 (t,J=7.16 Hz, 3H).

A 1 M solution of diisobutylaluminum hydride in tetrahydrofuran (8 mL)was added drop wise to a cooled (0° C.) solution of the above ester(0.650 g; 1.80 mmol) in dry tetrahydrofuran (50 mL). The reactionstirred at the temperature for 3 hours and then added saturated ammoniumchloride (30 ml). The resulting mixture was stirred for 30 min, and themixture was then added dichloromethane (150 ml) and hyflo super cellmedium (15 g). The resulting suspension was stirred at ambienttemperature 2 hours. The mixture was filtered and subsequentlyevaporated in vacuo. The crude product were taken up in dichloromethane(150 ml) and washed with water (2×50 ml). The dichloromethane phase wasdried with anhydrous magnesium sulfate and subsequently evaporated invacuo giving(Z)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-prop-2-en-1-olYield: 469 mg (82%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45-7.10 (m, 9H); 6.25 (t,J=6.78 Hz, 1H); 4.25 (d, J=6.78 Hz, 2H); 3.80 (s, 2H); 2.65 (s, 6H).

To a solution of the above alcohol (291 mg, 0.999 mmol) in drytetrahydrofuran (30 mL) was added tributylphosphine (0.27 ml, 1.5 mmol).The mixture was cooled to 0° C. and added1,1′-(azodicarbonyl)dipiperidine (377.5 mg, 1.5 mmol), and after 10 min(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (2151 mg, 1.1mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warmup to ambient temperature and stirred overnight. The reaction mixturewas added silica gel Fluka 60 (10 g) and evaporated in vacuo. Theresidue was purified by ISCO combiflash 16 (silica gel, hexane/ethylacetate 85:15) yielding(4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methyl-phenoxy)-aceticacid methyl ester as an oil.

Yield: 140 mg (30%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.45 (d, J=8.29 Hz, 2H) 7.25(m, 5H); 7.15 (d, J=8.29 Hz, 2H); 6.70-6.55 (m, 3H); 6.30 (t, 1H);4.55-4.45 (m, 4H); 3.80 (s, 2H); 3.45 (s, 3H); 2.39 (s, 6H); 2.25 (s,3H).

To a solution of the above ester (140 mg, 0.298 mmol) in ethanol (40 ml)was added 1N NaOH (0.6 ml) and the reaction mixture was stirred for 3hr. The mixture was evaporated in vacuo and the resulting residue wasdissolved in dichloromethane (50 mL) and extracted with water (10 ml).The aqueous phase was neutralized with 1N HCl (1 ml) and extracted withethyl acetate (20 ml). The ethyl acetate phase was dried with anhydrousmagnesium sulfate and evaporated in vacuo yielding the title acid aslight yellow solid.

Yield: 36 mg (27%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.44 (d, J=8.29 Hz, 2H) 7.26(m, 5H); 7.17 (d, J=8.29 Hz, 2H); 6.68-6.61 (m, 3H); 6.35 (t, 1H);4.51-4.42 (m, 4H); 3.88 (s, 2H); 2.67 (s, 6H); 2.25 (s, 3H).

Example 67(2-Methyl-4-{(Z)-3-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-phenoxy)aceticAcid

To a solution of (Z)-3-(4-lodo-phenyl)-3-phenyl-prop-2-en-1-ol (756 mg,2.249 mmol) in dry tetrahydrofuran (40 mL) was added tributylphosphine(0.61 ml, 3.37 mmol). The mixture was cooled to 0° C. and added1,1′-(azodicarbonyl)dipiperidine (850 mg, 3.37 mmol) and after 10 min(4-Hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (485 mg, 2.47mmol) was added. After 1.5 hr at 0° C. the reaction was allowed to warmup to ambient temperature and stirred overnight. The reaction mixturewas added silica gel Fluka 60 (10 g) and evaporated in vacuo. Theresidue was purified by ISCO combiflash 16 (silica gel, DCM/MeOH 90:10)giving(Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-aceticacid methyl ester as an oil.

Yield: 782 mg (68%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.29 Hz, 2H) 7.27(m, 5H); 6.95 (d, J=8.29 Hz, 2H); 6.68-6.61 (m, 3H); 6.31 (t, J=6.78 Hz1H); 4.58 (s, 2H); 4.50 (d, J=6.78 Hz, 2H); 3.80 (s, 3H); 2.25 (s, 3H).

A solution of(Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-aceticacid methyl ester (172 mg, 0.33 mmol), 4-prop-2-ynly-morpholine (0.9 ml,10.88 mmol), bis(triphenylphosphine) palladium(II) chloride (0.009 g,0.013 mmol), copper(I) iodide (0.19 mg, 0.001 mmol) in dry triethylamine(2 ml) were heated to 100° C. by microwave irradiation for 20 min. Thecooled reaction mixture was added dichloromethane (20 ml) and silica gelFluke 60 (10 g) and evaporated in vacuo. The residue was purified byISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding(2-Methyl-4-{(Z)-3-[4-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-phenoxy)-aceticacid methyl ester as an oil.

Yield: 78 mg (54%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.46 (d, J=8.29 Hz, 2H) 7.27(m, 5H); 7.20 (d, J=8.29 Hz, 2H); 6.68-6.58 (m, 3H); 6.30 (t, J=6.59 Hz1H); 4.58 (s, 2H); 4.50 (d, J=6.59 Hz, 2H); 3.80 (s, 3H); 3.75 (m, 4H);3.58 (s, 3H); 2.67 (m, 4H); 2.25 (s, 3H).

To a solution of the above ester (78 mg, 0.146 mmol) in ethanol (30 ml)was added 1N NaOH (0.43 ml) and stirred for 3 hr. The reaction mixturewas then evaporated in vacuo. The resulting residue was dissolved indichloromethane (50 mL) and extracted with water (10 ml). The aqueousphase was neutralized with 1N HCl (1 ml) and extracted with ethylacetate. The ethyl acetate phase was dried with anhydrous magnesiumsulfate and subsequently evaporated in vacuo yielding the title acid aslight yellow solid.

Yield: 67 mg (89%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.28 Hz, 2H), 7.26(m, 5H); 7.17 (d, J=8.28 Hz, 2H); 6.67-6.58 (m, 2H); 6.42 (m, 1H) 6.32(t, J=6.97 Hz, 1H); 4.57 (s, 2H); 4.45 (d, J=6.97 Hz, 2H); 3.82 (m, 4H);3.68 (s, 2H); 2.88 (m, 4H); 2.24 (s, 3H).

Example 68{2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-aceticAcid

A solution of(Z)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-aceticacid methyl ester (283 mg, 0.55 mmol), 2-Ethynyl-pyridine (0.167 ml.1.65 mmol), bis(triphenylphosphine) palladium(II) chloride (0.015 g,0.022 mmol), copper(I) iodide (0.31 mg, 0.002 mmol) in dry triethylamine(4 ml) were heated to 120° C. by microwave irradiation for 20 min. Thecooled reaction mixture was added dichloromethane (20 ml) and silica gelFluka 60 (10 g) and evaporated in vacuo. The residue was purified byISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) yielding{2-Methyl-4-[(Z)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-aceticacid methyl ester as a yellow solid.

Yield: 239 mg (88%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.63 (d, J=4.9 Hz, 1H), 7.70(m, 1H), 7.62 (d, J=7.91 Hz, 2H), 7.54 (d, J=7.51 Hz, 1H), 7.27 (m, 6H);7.21 (d, J=7.91 Hz, 2H); 6.61 (m, 3H); 6.32 (t, J=6.59 Hz, 1H); 4.58 (s,2H); 4.53 (d, J=6.97 Hz, 2H); 3.78 (s, 3H); 2.25 (s, 3H).

To a solution of the above ester (239 mg, 0.488 mmol) in methanol (40ml) was added 1N NaOH (0.975 ml, 0.975 mmol) and the mixture wererefluxed for 2 hr. After cooling to room temperature the mixture wereevaporated in vacuo. The residue was dissolved in dichloromethane (50mL) and extracted with water (10 ml). The aqueous phase was acidifiedwith 1N HCl (1 ml) pH 3 and extracted with dichloromethane (20 ml). Thedichloromethane phase were dried with anhydrous magnesium sulfate andsubsequently evaporated in vacuo yielding the title acid as light greenfoam.

Yield: 178 mg (76%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.65 (d, J=4.52 Hz, 1H), 7.74(m, 1H), 7.51 (m, 3H), 7.26 (m, 5H); 7.11 (d, J=7.91 Hz, 2H); 6.66 (m,2H); 6.45 (dd, J=8.85 and 3.2 Hz 1H) 6.35 (t, J=6.97 Hz, 1H); 4.63 (s,2H); 4.48 (d, J=6.97 Hz, 2H); 2.26 (s, 3H).

Example 69{2-Methyl-4-[(E)-3-phenyl-3-(4-pyridin-2-ylethynyl-phenyl)-allyloxy]-phenoxy}-aceticAcid

A solution of(E)-{4-[3-(4-iodo-phenyl)-3-phenyl-allyloxy]-2-methyl-phenoxy}-aceticacid methyl ester (250 mg, 0.55 mmol), 2-ethynyl-pyridine (0.147 ml,1.458 mmol), bis(triphenylphosphine) palladium(II) chloride (0.013 g,0.019 mmol), copper(I) iodide (0.27 mg, 0.001 mmol) in dry triethylamine(4 ml) were heated to 120° C. by microwave irradiation for 20 min. Thecooled reaction mixture was then added dichloromethane (20 ml) andsilica gel Fluka 60 (10 g) and evaporated in vacuo. The residue waspurified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15){2-methyl-4-[(E)-3-phenyl-3-(4-pyridin-2-ylethynylphenyl)-allyloxy]-phenoxy}-aceticacid methyl ester as a yellow oil.

Yield: 172 mg (73%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.63 (d, J=4.9 Hz, 1H), 7.68(m, 1H), 7.52 (m, 3H), 7.39 (m, 3H); 7.27 (m, 3H); 7.21 (d, 2H); 6.61(m, 3H); 6.32 (t, J=6.59 Hz, 1H); 4.58 (s, 2H); 4.53 (d, J=6.59 Hz, 2H);3.79 (s, 3H); 2.24 (s, 3H).

To a solution of the above ester (172 mg, 0.351 mmol) in methanol (30ml) was added 1N NaOH (0.700 ml) and the mixture were refluxed for 2 hr.The cooled mixture was evaporated in vacuo. The residue was dissolved indichloromethane (50 ml) and extracted with water (10 ml). The aqueousphase was acidified with 1N HCl (1 ml) pH 2 and extracted with ethylacetate. The ethyl acetate phase was dried with anhydrous magnesiumsulfate and subsequently evaporated in vacuo yielding the title acid aslight green foam.

Yield: 145 mg (87%).

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 8.65 (d, J=4.52 Hz, 1H), 7.74(m, 1H), 7.51 (m, 1H), 7.43 (m, 5H); 7.22 (m, 5H); 6.66 (m, 2H); 6.53(dd, J=8.67 and 3.01 Hz, 1H) 6.37 (t, J=6.59 Hz, 1H); 4.62 (s, 2H); 4.50(d, J=6.97 Hz, 2H); 2.25 (s, 3H).

Example 70(E)-[4-[3-(4-Bromophenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

(4-Ethynylphenyl)methanol (200 mg, 1.51 mmol) and diisopropylamine (360mg, 3.56 mmol) were added to a solution of methyl(Z)-[4-[3-(4-bromophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(445 mg, 0.75 mmol) in anhydrous tetrahydrofuran (15 mL). The solutionwas degassed and bis(triphenylphosphine)palladium(II) dichloride (30 mg,0.042 mmol) and copper(I) iodide (15 mg, 0.078 mmol) were added. Thereaction solution was degassed again and then stirred under inertatmosphere at ambient temperature over night. The reaction mixture wasfiltered through a paddle of silica gel; the paddle was thoroughlywashed with ethyl acetate (4×20 mL) and the combined filtrates wereconcentrated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, dichloromethane/methanol 98:2) yielding methyl(E)-[4-[3-(4-bromophenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 350 mg (78%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.57-7.53 (m, 4H); 7.42 (d,J=8.6 Hz, 2H); 7.36 (d, J=8.2 Hz, 2H); 7.18 (d, J=8.2 Hz, 2H); 7.12 (d,J=8.5 Hz, 2H); 6.67 (d, J=2.7 Hz, 1H); 6.62 (d, J=8.7 Hz, 1H); 6.57 (dd,J=8.9 and 2.8 Hz, 1H); 6.30 (t, J=6.6 Hz, 1H); 4.73 (s, 2H); 4.58 (s,2H); 4.51 (d, J=6.6 Hz, 2H); 3.79 (s, 3H); 2.25 (s, 3H).

A solution of lithium hydroxide monohydrate (60 mg, 1.22 mmol) indistilled water (2 mL) was added to a solution of the above ester (350mg, 0.59 mmol) in tetrahydrofuran (5 mL) and methanol (2 ml). Thesolution was stirred for 2 h and subsequently acidified with 2 Mhydrochloric acid to pH-4. The solution was diluted with ethyl acetate(20 mL) and water (15 mL); the phases were separated and the aqueousphase was extracted with ethyl acetate (3×15 mL). The combined organiclayers were washed with water (2×15 mL) and brine (2×15 mL), dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60,dichloromethane/methanol/acetic acid 98:8:0.5) affording the oil, whichwas triturated with hexanes (2×5 mL) giving the title acid as yellowamorphous solid.

Yield: 110 mg (32%).

M.p.: 125-133° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol/acetic acid 98:2:0.5): 0.50.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.61 (d, J=8.2 Hz, 2H);7.55-7.51 (m, 4H); 7.37 (d, J=8.2 Hz, 2H); 7.23 (d, J=8.1 Hz, 2H); 7.16(d, J=8.5 Hz, 2H); 6.61 (dd, J=8.6 and 2.7 Hz, 1H); 6.37 (t, J=6.6 Hz,1H); 4.58 (s, 2H); 4.53 (s, 2H); 4.48 (d, J=6.6 Hz, 2H); 2.13 (s, 3H).

Example 71(E)-1-[4-[4-[1-(4-Bromophenyl)-3-[4-(carboxymethoxy)-3-methylphenoxy]propenyl]-phenylethynyl]benzyl]piperidine-4-carboxylicAcid

Ethyl 1-ethynylpiperidine-4-carboxylate (260 mg, 1.43 mmol) anddiisopropylamine (340 mg, 3.36 mmol) were added to a solution of methyl(Z)-[4-[3-(4-bromophenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate(420 mg, 0.70 mmol) in anhydrous tetrahydrofuran (15 mL). The solutionwas degassed and bis(triphenylphosphine)palladium(II) dichloride (30 mg,0.042 mmol) and copper(I) iodide (15 mg, 0.078 mmol) were added. Thereaction solution was degassed again and then stirred under inertatmosphere at ambient temperature for 6 h. The reaction mixture wasfiltered through a paddle of silica gel; the paddle was thoroughlywashed with ethyl acetate (4×20 mL) and the combined filtrates wereconcentrated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, dichloromethane/methanol 99:1) yielding ethyl(E)-1-[4-[4-[1-(4-Bromophenyl)-3-[4-(carboxymethoxy)-3-methylphenoxy]propenyl]phenylethynyl]benzyl]piperidine-4-carboxylate.

Yield: 440 mg (96%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.85.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.48-7.42 (m, 4H); 7.16-7.11(m, 4H); 6.68 (d, J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8and 2.8 Hz, 1H); 6.30 (t, J=6.6 Hz, 1H); 4.60 (s, 2H); 4.50 (d, J=6.6Hz, 2H); 4.14 (q, J=7.1 Hz, 2H); 3.81 (s, 3H); 3.55 (s, 2H); 3.00-2.97(m, 2H); 2.40-2.29 (m, 3H); 2.26 (s, 3H); 2.02-1.97 (m, 2H); 1.91-1.81(m, 2H); 1.27 (t, J=7.1 Hz, 3H).

A solution of lithium hydroxide monohydrate (135 mg, 2.75 mmol) indistilled water (3 mL) was added to a solution of the above ester (440mg, 0.63 mmol) in tetrahydrofuran (5 mL) and methanol (2 ml). Thesolution was stirred for 4 h and then acidified with 2 M hydrochloricacid to pH˜6. The solution was diluted with ethyl acetate (20 mL) and10% aqueous solution of ammonium chloride (15 mL); the phases wereseparated and the aqueous phase was extracted with ethyl acetate (3×15mL). The combined organic layers were washed with 10% aqueous solutionof ammonium chloride (2×15 mL) and brine (2×15 mL), dried with anhydrousmagnesium sulfate and evaporated in vacuo. The residue was trituratedwith hexanes (2×7 mL) giving the title acid as yellow amorphous solid.

Yield: 120 mg (29%).

M.p.: 101-120° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 80:20): 0.05.

¹H NMR spectrum (300 MHz, DMSO-d₆, δ_(H)): 7.53 (d, J=8.5 Hz, 2H); 7.50(d, J=8.1 Hz, 2H); 7.19-7.14 (m, 4H); 6.72-6.69 (m, 2H); 6.60 (dd, J=8.8and 2.7 Hz, 1H); 6.36 (t, J=6.5 Hz, 1H); 4.58 (s, 2H); 4.46 (d, J=6.6Hz, 2H); 3.53 (s, 2H); 2.85-2.82 (m, 2H); 2.30-2.19 (m, 3H); 2.14 (s,3H); 1.86-1.81 (m, 2H); 1.63-1.51 (m, 2H).

Example 72(Z)-[4-[3-(4-Fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

Sodium methoxide (10 mg, 0.185 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (3.8 mL, 3.8 mmol) undernitrogen. The mixture was cooled to 0° C. and a solution of3-(4-bromophenyl)prop-2-yn-1-ol (800 mg, 3.79 mmol) in tetrahydrofuran(5 mL) was added over 20 min. The reaction mixture was stirred at 0° C.for 4 h; dry ethyl acetate (1.2 mL, 11.8 mmol) was added and the wholemixture was stirred at ambient temperature for further 30 min. Adegassed solution of 1-fluoro-4-iodobenzene (1 g, 4.51 mmol) in drytetrahydrofuran (10 mL), anhydrous zinc chloride (310 mg, 2.27 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (79 mg, 0.076mmol), and tri(2-furyl)phosphine (97 mg, 0.418 mmol) were added; themixture was degassed and then heated at 60° C. over night undernitrogen. The suspension was cooled down to ambient temperature,anhydrous methanol (1.9 mL) was added and the mixture was stirred foradditional 60 min. The resulting suspension was diluted with ether (20mL) and saturated aqueous solution of ammonium chloride (1.1 mL) wasadded. The mixture was filtered through a paddle of silica gel and thepaddle was thoroughly washed with ether (500 mL). The combined filtrateswere evaporated in vacuo and the residue was separated by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1-2:1)affording (E)-[3-(4-bromophenyl)-3-(4-fluorophenyl)prop-2-en-1-ol asoil.

Yield: 260 mg (22%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.6 Hz, 2H);7.15-7.04 (m, 6H); 6.22 (t, J=6.8 Hz, 1H); 4.21 (d, J=6.7 Hz, 2H).

The above allyl alcohol (260 mg, 0.847 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (183 mg, 0.933 mmol) andtriphenylphosphine (267 mg, 1.02 mmol) were dissolved in a mixture ofanhydrous toluene (15 mL) and tetrahydrofuran (5 mL). The solution wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.2 mL, 1.01 mmol) in anhydroustetrahydrofuran (4 mL) was added dropwise over 10 min. The reactionmixture was allowed to warm up to the ambient temperature with the bathand then was stirred for 18 h. The solvents were evaporated in vacuo andthe residue was separated by flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 9:1) affording methyl(E)-[4-[3-(4-bromophenyl)-3-(4-fluorophenyl)allyloxy]-2-methylphenoxy]acetateas yellow solid.

Yield: 278 mg (68%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.39 (d, J=8.7 Hz, 2H);7.16-7.03 (m, 6H); 6.65 (d, J=2.9 Hz, 1H); 6.60 (d, J=8.8 Hz, 1H); 6.54(dd, J=8.9 and 2.9 Hz, 1H); 6.26 (t, J=6.7 Hz, 1H); 4.56 (s, 2H); 4.45(d, J=6.7 Hz, 2H); 3.76 (s, 3H); 2.22 (s, 3H).

In atmosphere of nitrogen, the above bromo derivate (278 mg, 0.573 mmol)and N-propargylmorpholine (115 mg, 0.920 mmol) were dissolved inanhydrous tetrahydrofuran (8 mL). The solution was degassed; copper(I)iodide (7 mg, 0.037 mmol), bis(tri-t-butylphosphine)palladium (15 mg,0.029 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL, 0.742 mmol)were subsequently added. The mixture was stirred under nitrogen at 60°C. for 18 h, cooled down and evaporated in vacuo. The residue waspurified by flash column chromatography (silica gel Fluka 60,dichloromethane/methanol 98:2) yielding methyl(Z)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetateas brownish oil.

Yield: 218 mg (72%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.36 (d, J=8.5 Hz, 2H);7.19-7.05 (m, 6H); 6.68 (d, J=2.9 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57(dd, J=8.9 and 2.7 Hz, 1H); 6.32 (t, J=6.6 Hz, 1H); 4.58 (s, 2H); 4.49(d, J=6.7 Hz, 2H); 3.79 (s, 3H); 3.78 (m, 4H (overlapped)); 3.51 (s,2H); 2.64 (m, 4H); 2.25 (s, 3H).

To a solution of the above ester (218 mg, 0.412 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (52 mg, 1.24 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.071 mL, 1.24 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL). The combinedorganic layers were washed with water (2×20 mL) and brine (2×20 mL),dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (2×5 mL) yielding the title acid aswhite solid.

Yield: 120 mg (57%).

M.p.: 144-149° C.

R_(F) (SiO₂, dichloromethane/methanol 90:10): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.31 (d, J=8.4 Hz, 2H);7.16-7.04 (m, 6H); 6.67 (d, J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.42(dd, J=9.0 and 2.8 Hz, 1H); 6.30 (t, J=6.7 Hz, 1H); 4.54 (s, 2H); 4.43(d, J=6.7 Hz, 2H); 3.82 (m, 4H); 3.63 (s, 2H); 2.83 (m, 4H); 2.24 (s,3H).

Example 73(E)-[2-Methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-phenoxy]aceticAcid

Sodium methoxide (11 mg, 0.204 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (3.9 mL, 3.9 mmol) undernitrogen. The mixture was cooled to 0° C. and a solution of3-(4-bromophenyl)prop-2-yn-1-ol (820 mg, 3.89 mmol) in tetrahydrofuran(5 mL) was added over 15 min. The reaction mixture was stirred at 0° C.for 3 h; dry ethyl acetate (1.2 mL, 12.1 mmol) was added and the wholemixture was stirred at ambient temperature for 30 min. A degassedsolution of 1-iodo-4-methylbenzene (1.02 g, 4.68 mmol) in drytetrahydrofuran (10 mL), anhydrous zinc chloride (318 mg, 2.33 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (81 mg, 0.078mmol), and tri(2-furyl)phosphine (99 mg, 0.426 mmol) were added; themixture was degassed and then heated at 60° C. over night undernitrogen. The suspension was cooled down to ambient temperature,anhydrous methanol (1.95 mL) was added and the resulting mixture wasstirred for additional 60 min. The reaction was diluted with ether (20mL) and saturated aqueous solution of ammonium chloride (1.15 mL) wasadded. The mixture was filtered through a paddle of silica gel and thepaddle was thoroughly washed with ether (500 mL). The solvents wereevaporated in vacuo and the residue was separated by flash columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 4:1)affording (E)-[3-(4-bromophenyl)-3-(4-methylphenyl)prop-2-en-1-ol asyellow solid.

Yield: 192 mg (16%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.39 (d, J=8.8 Hz, 2H); 7.17(m, 2H); 7.11 (d, J=8.7 Hz, 2H); 7.01 (d, J=8.0 Hz, 2H); 6.18 (t, J=6.8Hz, 1H); 4.21 (d, J=6.8 Hz, 2H); 2.37 (s, 3H).

The above allyl alcohol (192 mg, 0.633 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (137 mg, 0.698 mmol) andtriphenylphosphine (199 mg, 0.759 mmol) were dissolved in a mixture ofanhydrous toluene (15 mL) and tetrahydrofuran (5 mL). The solution wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.15 mL, 0.757 mmol) in anhydroustetrahydrofuran (4 mL) was added dropwise over 10 min. The reactionmixture was allowed to warm up to the ambient temperature with the bathand then was stirred for 19 h. The solvents were evaporated in vacuo andthe residue was separated by flash column chromatography (silica gelFluka 60, hexanes/ethyl acetate 9:1) affording methyl(E)-[4-[3-(4-bromophenyl)-3-(4-methylphenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 156 mg (51%).

R_(F) (SiO₂, hexanes/ethyl acetate 2:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.41 (d, J=8.5 Hz, 2H); 7.20(d, J=7.8 Hz, 2H); 7.14 (d, J=8.6 Hz, 2H); 7.07 (d, J=8.1 Hz, 2H); 6.68(d, J=2.8 Hz, 1H); 6.63 (d, J=8.7 Hz, 1 H); 6.57 (dd, J=8.9 and 2.8 Hz,1H); 6.25 (t, J=6.6 Hz, 1H); 4.58 (s, 2H); 4.53 (d, J=6.6 Hz, 2H); 3.79(s, 3H); 2.40 (s, 3H); 2.25 (s, 3H).

In atmosphere of nitrogen, the above bromo derivate (156 mg, 0.324 mmol)and N-propargylmorpholine (65 mg, 0.520 mmol) were dissolved inanhydrous tetrahydrofuran (8 mL). The solution was degassed; copper(I)iodide (4 mg, 0.021 mmol), bis(tri-t-butylphosphine)palladium (8.5 mg,0.017 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.063 mL, 0.421mmol) were subsequently added. The mixture was stirred under nitrogen at60° C. for 17 h, cooled down and evaporated in vacuo. The residue waspurified by flash column chromatography (silica gel Fluka 60,dichloromethane/methanol 98:2) yielding methyl(E)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]phenoxy]acetateas brownish oil.

Yield: 157 mg (92%).

R_(F) (SiO₂, dichloromethane/methanol 95:5): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.35 (d, J=8.5 Hz, 2H); 7.20(d, J=8.4 Hz, 4H); 7.07 (d, J=8.0 Hz, 2H); 6.68 (d, J=2.8 Hz, 1H); 6.63(d, J=8.8 Hz, 1H); 6.57 (dd, J=8.9 and 2.8 Hz, 1H); 6.27 (t, J=6.6 Hz,1H); 4.58 (s, 2H); 4.53 (d, J=6.6 Hz, 2H); 3.79 (s, 3H); 3.78 (m, 4H(overlapped)); 3.52 (s, 2H); 2.65 (m, 4H); 2.39 (s, 3H); 2.24 (s, 3H).

To a solution of the above ester (157 mg, 0.299 mmol) intetrahydrofuran/methanol mixture (5:1.6 mL), a solution of lithiumhydroxide monohydrate (38 mg, 0.906 mmol) in distilled water (1 mL) wasadded under cooling to 0° C. The solution was stirred for 1.5 h undercooling, acetic acid (0.052 mL, 0.909 mmol) was added and the resultingmixture was stirred for further 10 min. The solution was diluted withchloroform (40 mL) and water (30 mL); the phases were separated and theaqueous phase was extracted with chloroform (3×20 mL). The combinedorganic layers were washed with water (2×20 mL) and brine (2×20 mL),dried with anhydrous magnesium sulfate and evaporated in vacuo. Thisafforded the title acid as yellow solid.

Yield: 77 mg (50%).

M.p.: 109-118° C.

R_(F) (SiO₂, dichloromethane/methanol 90:10): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.30 (d, J=8.2 Hz, ˜2H(overlapped)); 7.17 (m, 4H); 7.06 (d, J=7.8 Hz, 2H); 6.67 (d, J=2.5 Hz,1H); 6.62 (d, J=9.0 Hz, 1H); 6.45 (dd, J=8.4 and 2.7 Hz, 1H); 6.26 (t,J=6.5 Hz, 1H); 4.54 (s, 2H); 4.48 (d, J=6.6 Hz, 2H); 3.81 (m, ˜4H); 3.62(s, 2H); 2.81 (m, 4H); 2.38 (s, 3H); 2.24 (s, 3H).

Example 74(Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

1 M Solution of lithium aluminum hydride in tetrahydrofuran (7.9 mL, 7.9mmol) was added to sodium methoxide (21 mg, 0.396 mmol) under nitrogen.The mixture was cooled to 0° C. and a solution of3-(4-bromophenyl)-prop-2-yn-1-ol (1.67 g, 7.91 mmol) in drytetrahydrofuran (12 mL) was added dropwise. The reaction mixture wasstirred at 0° C. for 3.5 h; dry ethyl acetate (2.4 mL, 15.8 mmol) wasadded and the whole mixture was stirred at ambient temperature for 30min. A degassed solution of 1-chloro-4-iodobenzene (1.89 g, 7.91 mmol)in anhydrous tetrahydrofuran (12 mL), anhydrous zinc chloride (0.65 g,4.77 mmol), tris(dibenzylidene-acetone)dipalladium chloroform complex(0.165 g, 0.16 mmol) and tri-(2-furyl)phosphine (0.184 g, 0.791 mmol)were added; the mixture was degassed and stirred at 65° C. for 22 hunder atmosphere of nitrogen. The suspension was cooled down; methanol(3.5 mL) was added and the mixture was stirred for additional 1 h. Themixture was diluted with ether (40 mL) and saturated aqueous solution ofammonium chloride (2 mL), was filtered through a pad of silica gel andthe pad was thoroughly washed with ether (80 mL). the filtrate wasevaporated in vacuo and the residue was purified by flash columnchromatography (silica gel Fluka 60, dichloromethane/ethyl acetate 20:1)affording (E)-3-(4-bromophenyl)-3-(4-chlorophenyl)-prop-2-en-1-ol asyellow oil, which solidified in fridge.

Yield: 0.540 g (21%).

R_(F) (SiO₂, ethyl acetate/hexane 20:1): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.7 Hz, 2H); 7.36(d, J=8.7, 2H); 7.10 (d, J=8.7 Hz, 2H); 7.09 (d, J=8.7 Hz, 2H); 6.25 (t,J=6.8 Hz, 1H); 4.20 (d, J=6.8 Hz, 2H).

The above allyl alcohol (0.28 g, 0.865 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.187 g, 0.952 mmol) andtriphenylphosphine (0.261 g, 0.995 mmol) were dissolved in a mixture ofanhydrous toluene (3 mL) and tetrahydrofuran (1.5 mL). The mixture wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (0.196 mL, 0.995 mmol) in anhydroustetrahydrofuran (1 mL) was added dropwise. The reaction mixture wasallowed to warm up to ambient temperature and then was stirred overnight.

The solvents were evaporated in vacuo and the residue was submitted toflash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate6:1) affording(E)-[4-[3-(4-bromophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenoxy]acetateas yellow oil.

Yield: 270 mg (62%).

R_(F) (SiO₂, hexanes/ethyl acetate 6:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.7 Hz, 2H); 7.36(d, J=8.7, 2H); 7.10 (d, J=8.7 Hz, 2H); 7.09 (d, J=8.7 Hz, 2H); 6.67 (d,J=2.8 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.8 Hz, 1H);6.30 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.47 (d, J=6.7 Hz, 2H); 3.79 (s,3H); 2.25 (s, 3H).

To a degassed solution of the above ester (270 mg, 0.538 mmol),N-propargylmorpholine (101 mg, 0.807 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.322 mL, 2.15 mmol) in anhydroustetrahydrofuran (5 mL), bis(tri-t-butylphosphine)palladium (15 mg, 0.03mmol) and copper(I) iodide (8 mg, 0.04 mmol) were added. The reactionmixture was stirred at 50° C. for 20 h under nitrogen. The solvents wereevaporated in vacuo and the residue was purified by flash columnchromatography (silica gel Fluka 60, chloroform/methanol 100:0-98:2)yielding methyl(Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetateas yellow oil.

Yield: 200 mg (68%).

R_(F) (SiO₂, chloroform/methanol 95:5): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.37 (d, J=8.4 Hz, 2H); 7.36(d, J=8.4 Hz, 2H); 7.18 (d, J=8.4 Hz, 2H); 7.13 (d, J=8.4 Hz, 2H); 6.67(d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.57 (dd, J=8.8 and 2.8 Hz,1H); 6.33 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.48 (d, J=6.7 Hz, 2H); 3.77(m, 7H); 3.51 (s, 2H); 2.64 (m, 2H); 2.25 (s, 3H).

The above ester (200 mg, 0.37 mmol) was dissolved in a mixture oftetrahydrofuran (6 mL) and methanol (4 mL) and a solution of lithiumhydroxide monohydrate (35 mg, 0.83 mmol) in distilled water (2 mL) wasadded. The mixture was stirred over night and then diluted withsaturated aqueous solution of ammonium chloride (45 mL). The resultingmixture was extracted with ether (3×30 mL); the combined organic layerswere dried with anhydrous magnesium sulfate and evaporated in vacuo. Theresidue was triturated with hexanes (2×10 mL) yielding the title acid asyellowish powder.

Yield: 120 mg (62%).

M.p.: 92-95° C.

R_(F) (SiO₂, chloroform/methanol 4:1): 0.50.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.38 (d, J=4.7 Hz, 2H); 7.35(d, J=4.8 Hz, 2H); 7.19 (d, J=8.3 Hz); 7.13 (d, J=8.3 Hz, 2H); 6.68-6.64(m, 2H, overlapped); 6.56 (dd, J=8.8 and 2.7 Hz, 1H); 6.33 (t, J=6.7 Hz,1H); 4.59 (s, 2H); 4.48 (d, J=6.6 Hz, 2H); 3.84 (t, J=4.4 Hz, 4H); 3.71(s, 2H); 2.89 (t, J=4.4 Hz, 4H); 2.25 (s, 3H).

Example 75 Methyl(E)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate

To a degassed solution of 1-bromo-4-trifluoromethylbenzene (17.7 g, 78.6mmol) in tetrahydrofuran (140 mL) was added in the following order:copper(I) iodide (447 mg, 2.35 mmol),bis(triphenylphosphine)palladium(II) dichloride (1.65 g, 2.35 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (14.4 g, 94.3 mmol). The resultingmixture was degassed one more time, cooled in an ice bath and a solutionof propargyl alcohol (5.29 g, 94.3 mmol) in tetrahydrofuran (5 mL) wasadded over period of 10 min. The reaction mixture was slowly heated upto 55° C. and then stirred at this temperature for 3 h and subsequentlyat ambient temperature overnight. The mixture was diluted with ether(200 mL), washed with 5% hydrochloric acid (60 mL), water (3×50 mL) andsaturated aqueous solution of sodium hydrogen carbonate (30 mL). Theorganic solution was dried with anhydrous magnesium sulfate andevaporated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, dichloromethane) yielding3-(4-trifluoromethylphenyl)prop-2-yn-1-ol.

Yield: 15.1 g (˜100%).

R_(F) (SiO₂, chloroform): 0.25.

Sodium methoxide (0.375 g, 6.95 mmol) was added to 1 M solution oflithium aluminum hydride in tetrahydrofuran (146 mL, 146 mmol) underatmosphere of argon. The mixture was cooled to 0° C. and a solution ofthe above alcohol (27.8 g, 139 mmol) in tetrahydrofuran (210 mL) wasadded over 70 min. The reaction was stirred at 0° C. for 3 h; drydimethyl carbonate (14.5 g, 161 mmol) was added under cooling and thenthe whole mixture was stirred at ambient temperature for 15 min. Adegassed solution of 1,4-diiodobenzene (50.5 g, 153 mmol) in drytetrahydrofuran (120 mL), anhydrous zinc chloride (11.4 g, 83.3 mmol),tris(dibenzylideneacetone)dipalladium chloroform complex (2.88 g, 2.78mmol), and tri(2-furyl)phosphine (3.55 g, 15.3 mmol) were added; themixture was degassed and then heated at 65° C. for 15 h under argon. Thesuspension was cooled down; methanol (75 mL) was added and the mixturewas stirred for additional 1 h. Saturated solution of ammonium chloridewas added (40 mL), the reaction mixture was diluted with water (200 mL),acidified with 5% hydrochloric acid under stirring. Ether was added(1000 mL) and the mixture was filtered through a pad of silica gel andthe pad was thoroughly washed with ether (3×100 mL). The combinedfiltrates were evaporated in vacuo and the residue was purified bycolumn chromatography (silica gel Fluka 60, dichloromethane) and theobtained crude product (55 g) was crystallized fromethanol/toluene/n-heptane mixture. This afforded(Z)-3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)prop-2-en-1-ol as yellowcrystals.

Yield: 26.9 g (48%).

M.p.: 109-111° C.

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.3 Hz, 2H); 7.55(d, J=8.1 Hz, 2H); 7.34 (d, J=8.1 Hz, 2H); 6.90 (d, J=8.3 Hz, 2H); 6.31(t, J=6.8 Hz, 1H); 4.24 (d, J=6.8 Hz, 2H).

The above allyl alcohol (11.88 g, 29.4 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (6.34 g, 32.3 mmol) andtriphenylphosphine (9.25 g, 35.3 mmol) were dissolved in a mixture ofanhydrous tetrahydrofuran (200 mL) and toluene (550 mL). The mixture wascooled to 0° C., kept under nitrogen and a degassed solution ofdiisopropyl azodicarboxylate (7.36 mL, 35.3 mmol) in anhydroustetrahydrofuran (50 mL) was added dropwise during 70 min. The reactionmixture was allowed to warm up to ambient temperature with the bath andthen stirred overnight. The solvents were evaporated in vacuo and theresidue was submitted to column chromatography (silica gel Fluka 60,hexanes/ethyl acetate 85:15) affording methyl(Z)-[4-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-2-methylphenoxy]acetateas solidifying yellow oil.

Yield: 14.1 g (82%).

R_(F) (SiO₂, hexanes/ethyl acetate 3:1): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.74 (d, J=8.4 Hz, 2H); 7.55(d, J=8.1 Hz, 2H); 7.35 (d, J=8.1 Hz, 2H); 6.93 (d, J=8.4 Hz, 2H);6.69-6.55 (m, 3H); 6.37 (t, J=6.6 Hz, 1H); 4.59 (s, 2H); 4.51 (d, J=6.6Hz, 2H); 3.79 (s, 3H); 2.26 (s, 3H).

A solution of the above ester (13.9 g, 23.9 mmol), N-propargylmorpholine(5.98 g, 47.7 mmol) and N,N-diisopropylamine (11.35 g, 112 mmol) intetrahydrofuran (250 mL) was cooled down and degassed;bis(triphenylphosphine)palladium(II) dichloride (0.84 g, 1.19 mmol) andcopper(I) iodide (0.365 g, 1.9 mmol) were added. The reaction mixturewas stirred at ambient temperature for 18 h. The mixture was evaporatedin vacuo and the residue was purified by column chromatography (silicagel Fluka 60, hexanes/ethyl acetate/methanol 64:32:4) yielding the titlecompound as a white crystals.

Yield: 13.2 g (71%).

M.p.: 83-85° C.

R_(F) (SiO₂, hexanes/ethyl acetate/methanol 64:32:4): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.54 (d, J=8.3 Hz, 2H); 7.48(d, J=8.3 Hz, 2H); 7.35 (d, J=8.5 Hz, 2H); 7.14 (d, J=8.3 Hz, 2H);6.68-6-55 (m, 3H); 6.37 (t, J=6.7 Hz, 1H); 4.59 (s, 2H); 4.53 (d, J=6.7Hz, 2H); 3.80 (s, 3H); 3.77 (m, 4H); 3.54 (s, 2H); 2.66 (m, 4H); 2.25(s, 3H).

Example 76(Z)-[4-[3-(4-Chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]-propionicAcid

Ethyl 4-hydroxy-2-methylphenylpropionate (0.21 g, 1.0 mmol),(E)-[3-(4-bromophenyl)-3-(4-chlorophenyl)]allyl alcohol (0.26 g, 0.80mmol) and triphenylphosphine (0.29 g, 1.1 mmol) were dissolved in amixture of anhydrous toluene (5 mL) and tetrahydrofuran (5 mL). Themixture was cooled to 0° C., kept under nitrogen and diisopropylazodicarboxylate (0.25 g, 1.17 mmol) was added dropwise. The reactionmixture was stirred at 0° C. for 3 h and then left to stand at ambienttemperature for 1 week. The solvents were evaporated in vacuo and theresidue was submitted to column chromatography (silica gel Fluka 60,benzene) affording ethyl(E)-[4-[3-(4-bromophenyl)-3-(4-chlorophenyl)allyloxy]-2-methylphenyl]-propionate.

Yield: 0.28 g (68%).

R_(F) (SiO₂, benzene): 0.30.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.42 (d, J=8.6 Hz, 2H); 7.37(d, J=8.5 Hz, 2H); 7.12 (t, 4H); 7.01 (d, J=8.3 Hz, 1H); 6.64 (d, J=2.5Hz, 1H); 6.61 (dd, J=8.3 and 2.5 Hz, 1H); 6.31 (t, J=6.6 Hz, 1H); 4.50(d, J=6.6 Hz, 2H); 4.13 (q, J=7.1 Hz, 2H); 2.86 (t, J=8.4 Hz, 2H); 2.52(t, J=8.4 Hz, 2H); 2.27 (s, 3H); 1.24 (t, J=7.1 Hz, 3H).

Under nitrogen atmosphere, 4-propargylmorpholine (550 mg, 4.4 mmol)bis(triphenylphosphine)palladium(II) dichloride (40 mg, 0.057 mmol) andcopper(II) acetate (7 mg, 0.038 mmol) were added to a degassed solutionof the above ester (280 mg, 0.55 mmol) in triethylamine (30 mL). Thereaction mixture was refluxed for 8 h, diluted with benzene (100 mL),filtered and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, chloroform/methanol 9:1) yieldingethyl(Z)-[4-[3-(4-chlorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenyl]propionate.

Yield: 0.20 g (66%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.65.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.36 (t, 4H); 7.18 (d, J=8.4Hz, 2H); 7.14 (d, J=8.4 Hz, 2H); 7.01 (d, J=8.3 Hz, 1H); 6.64 (d, J=2.5Hz, 1H); 6.60 (dd, J=8.3 and 2.5 Hz, 1H); 6.34 (t, J=6.6 Hz, 1H); 4.51(d, J=6.6 Hz, 2H); 4.12 (q, J=7.1 Hz, 2H); 3.77 (bt, 4H); 3.51 (s, 2H);2.86 (t, J=7.4 Hz, 2H); 2.64 (bt, 4H); 2.52 (t, J=7.4 Hz, 2H) 2.27 (s,3H); 1.24 (t, J=7.1 Hz, 3H).

The above ester (0.20 g, 0.358 mmol) was dissolved in ethanol (20 mL), asolution of lithium hydroxide monohydrate (0.06 g, 1.43 mmol) in water(2 mL) was added and the mixture was left to stand for 48 h. Thesolvents were evaporated in vacuo; the residue was diluted with water(25 mL) and extracted with ether (10 mL). The ethereal extract wasdiscarded, the aqueous layer was acidified with acetic acid (0.5 mL) andthe separated title compound was filtered off and dried in the air.

Yield: 0.15 g (79%).

R_(F) (SiO₂, chloroform/methanol 3:1): 0.80.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.34 (t, 4H); 7.18 (d, J=8.4Hz, 2H); 7.13 (d, J=8.4 Hz, 2H); 7.03 (d, J=8.4 Hz, 1H); 6.64 (d, J=2.4Hz, 1H); 6.60 (dd, J=8.4 and 2.4 Hz, 1H); 6.34 (t, J=6.6 Hz, 1H); 4.51(d, J=6.6 Hz, 2H); 3.78 (bt, 4H); 3.54 (s, 2H); 2.87 (t, J=7.7 Hz, 2H);2.69 (bt, 4H); 2.57 (t, J=7.7 Hz, 2H) 2.27 (s, 3H).

Example 77(Z)-[2-Methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-phenoxy]aceticAcid

Sodium methoxide (23 mg, 0.43 mmol) was added to 1 M solution of lithiumaluminum hydride in tetrahydrofuran (9 mL, 9.0 mmol). The mixture wascooled to 0° C. and a solution of 3-(4-bromophenyl)prop-2-yn-1-ol (1.9g, 9.0 mmol) in tetrahydrofuran (15 mL) was slowly added. The reactionwas stirred for at 0° C. for 3 h; ethyl acetate (2.7 mL, 9.0 mmol) wasadded and the mixture was stirred for 10 min without cooling.4-Iodobenzotrifluoride (2.33 g, 8.6 mmol), anhydrous zinc chloride (0.74g, 5.4 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex(0.19 g, 0.18 mmol) and tri(2-furyl)phosphine (0.17 g, 0.73 mmol) wereadded, the mixture was evacuated and kept under nitrogen. The mixturewas heated at 65° C. for 16 h. Methanol (4.5 mL) was added and themixture was stirred for additional 1 h. The reaction mixture was dilutedwith ether (300 mL) and saturated aqueous solution of ammonium chloride(2.5 mL) was added. The mixture was filtered through a pad of silicagel, evaporated in vacuo and the residue was submitted to columnchromatography (silica gel Fluka 60, hexanes/ethyl acetate 80:20)affording(E)-3-(4-bromophenyl)-3-(4-trifluoromethylphenyl)-prop-2-en-1-ol.

Yield: 0.77 g (24%).

R_(F) (SiO₂, hexanes/ethyl acetate 70:30): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.65 (d, J=7.9 Hz, 2H); 7.43(d, J=8.7 Hz, 2H); 7.28 (d, J=7.9 Hz, 2H); 7.08 (d, J=8.6 Hz, 2H); 6.30(t, J=6.9 Hz, 1H); 4.19 (d, J=6.7 Hz, 2H).

The above allyl alcohol (0.77 g, 2.16 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.47 g, 2.37 mmol) andtriphenylphosphine (0.68 g, 2.59 mmol) were dissolved in a mixture ofanhydrous toluene (10 mL) and tetrahydrofuran (3 mL). The mixture wasdegassed, cooled to 0° C. and a degassed solution of diisopropylazodicarboxylate (0.525 g, 2.60 mmol) in anhydrous tetrahydrofuran (3mL) was added dropwise under nitrogen. The reaction mixture was stirredat ambient temperature over night. The solvents were evaporated in vacuoand the residue was submitted to column chromatography (silica gel Fluka60, hexanes/ethyl acetate 95: 5-90:10) affording methyl(E)-[4-[3-(4-bromophenyl)-3-[4-trifluoromethylphenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 0.84 g (73%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.66 (d, J=8.0 Hz, 2H); 7.43(d, J=8.5 Hz, 2H); 7.31 (d, J=7.9 Hz, 2H); 7.09 (d, J=8.5 Hz, 2H); 6.67(d, J=2.7 Hz, 1H); 6.63 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.9 Hz,1H); 6.37 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.46 (d, J=6.7 Hz, 2H); 3.79(s, 3H); 2.25 (s, 3H).

Under nitrogen atmosphere, N-propargylmorpholine (160 mg, 1.28 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (480 mg, 1.73 mmol) were added to adegassed solution of the above compound (420 mg, 0.78 mmol) intetrahydrofuran (10 mL). Bis(tri-tert-butylphosphine)palladium (20 mg,0.04 mmol) and copper(I) iodide (10 mg, 0.05 mmol) were added; thereaction mixture was degassed again and then stirred at ambienttemperature over night under inert atmosphere. The reaction mixture wasfiltered through a pad of silica gel; the pad was washed with ethylacetate (4×15 mL) and the combined organic filtrates were evaporated invacuo. The residue was purified by repeated column chromatography(silica gel Fluka 60, hexanes/ethyl acetate 1:1 and thendichloromethane/ethyl acetate/methanol 72:25:3) yielding methyl(Z)-[2-methyl-4-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]phenoxy]acetate.

Yield: 190 mg (42%).

R_(F) (SiO₂, dichloromethane/ethyl acetate/methanol 20:10:1): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.65 (d, J=8.0 Hz, 2H); 7.36(d, J=8.0 Hz, 2H); 7.32 (d, J=8.0 Hz, 2H); 7.16 (d, J=8.2 Hz, 2H); 6.67(d, J=2.4 Hz, 1H); 6.62 (d, J=8.8 Hz, 1H); 6.56 (dd, J=8.8 and 2.7 Hz,1H); 6.39 (t, J=6.7 Hz, 1H); 4.58 (s, 2H); 4.47 (d, J=6.7 Hz, 2H); 3.78(s, 3H, overlapped); 3.78-3.76 (m, 4H, overlapped); 3.51 (s, 2H);2.65-2.62 (m, 4H); 2.25 (s, 3H).

A solution of the above ester (0.19 g, 0.33 mmol) in a mixture oftetrahydrofuran (5 mL) and methanol (2 mL) was cooled to 0° C. Asolution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) indistilled water (1.5 mL) was added and the mixture was stirred for 2 h.The reaction mixture was acidified with 2 M hydrochloric acid to pH-6and then diluted with 10% aqueous solution of ammonium chloride (20 mL)and ethyl acetate (20 mL). The phases were separated, the aqueous phasewas washed with ethyl acetate (4×15 mL); the combined organic extractswere washed with 10% aqueous solution of ammonium chloride (2×15 mL) andbrine (2×15 mL), dried with anhydrous magnesium sulfate and concentratedin vacuo. The residue was triturated with hexanes (2×10 mL) yielding thetitle compound as amorphous white solid.

Yield: 0.160 g (86%).

R_(F) (SiO₂, chloroform/methanol 90:10): 0.15.

M.p.: 96-100° C.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.64 (d, J=8.1 Hz, 2H);7.33-7.28 (m, 4H); 7.13 (d, J=8.4 Hz, 2H); 6.65 (d, J=2.8 Hz, 1H); 6.62(d, J=8.9 Hz, 1H); 6.45-6.36 (m, 2H); 4.53 (s, 2H); 4.41 (d, J=6.7 Hz,2H); 3.84-3.81 (m, 4H); 3.66 (s, 2H); 2.85 (bs, 4H), 2.24 (s, 3H).

Example 78(Z)-[4-[3-(Benzo[b]thiophen-2-yl)-3-[4-[4-(trifluoromethylphenyl)ethynyl]phenyl]allyloxy]-2-methyl-phenoxy]aceticAcid

(Z)-3-(4-Bromophenyl)-3-iodoprop-2-en-1-ol (0.950 g, 2.8 mmol), carbontetrabromide (0.913 g, 3 mmol) and triphenylphosphine (0.786 g, 3 mmol)were mixed in anhydrous dichloromethane (10 mL) and the mixture wasstirred at 0° C. for 3 h and then at 20° C. overnight. Ether (50 mL) andhexanes (30 mL) were added and the mixture was filtrated through apaddle of silica to remove precipitated triphenylphosphine oxide.Solvents were removed by evaporation in vacuo and crude1-bromo-4-((Z)-3-bromo-1-iodopropenyl)benzene was prepared inquantitative yield and was subsequently used without furtherpurification.

Yield: 1.20 g (100%).

R_(F) (SiO₂, hexanes/ethyl acetate 9:1) 0.90.

The above allyl bromide (0.787 g, 1.96 mmol), methyl(4-hydroxy-2-methylphenoxy)acetate (0.652 g, 2.00 mmol) and cesiumcarbonate (0.652 g, 2.00 mmol) were stirred at 20° C. overnight. Themixture was filtered and evaporated in vacuo. The residue was submittedto column chromatography (silica gel Fluka 60, hexanes/ethyl acetate95:5) affording methyl(Z)-[4-[3-(4-bromophenyl)-3-iodoallyloxy]-2-methylphenoxy]acetate.

Yield: 0.722 g (71%).

R_(F) (SiO₂, hexanes/ethyl acetate 9:1) 0.35

Methyl (Z)-[4-[3-(4-bromophenyl)-3-iodoallyloxy]-2-methylphenoxy]acetate(760 mg, 1.47 mmol) and (benzo[b]thiophen-2-yl)-tributyltin (0.72 g, 1.7mmol) were dissolved in anhydrous N,N-dimethylformamide (20 mL) and thesolution was degassed. 0.15 M solution of trit-butylphosphine incyclohexane (1.2 mL, 0.18 mmol) and tris(dibenzylidenacetone)dipalladiumchloroform complex (46 mg, 0.044 mmol) were added; the reaction solutionwas degassed again and then stirred under inert atmosphere at 50° C. for2 h. The reaction mixture was diluted with ethyl acetate (50 mL) andextracted with 10% aqueous solution of potassium fluoride (50 mL), water(2×50 mL) and brine (2×30 mL). The organic layer was dried withanhydrous magnesium sulfate and evaporated in vacuo. The residue waspurified by column chromatography (silica gel Fluka 60, hexanes/ethylacetate 95:5-90:10) yielding methyl(Z)-[4-[3-(benzo[b]thiophen-2-yl)-3-(4-bromophenyl)allyloxy]-2-methylphenoxy]acetate.

Yield: 530 mg (68%).

R_(F) (hexanes/ethyl acetate 80:20): 0.45.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.84-7.77 (m, 2H); 7.45 (d,J=8.6 Hz, 2H); 7.39-7.35 (m, 2H); 7.27-7.22 (m, 2H); 6.73 (bs, 1H);6.63-6.61 (m, 2H); 6.34 (t, J=6.3 Hz, 1H); 4.76 (d, J=6.3 Hz, 2H); 4.58(s, 2H); 3.79 (s, 3H); 2.25 (s, 3H).

Under nitrogen atmosphere, 1-ethynyl-4-trifluoromethylbenzene (135 mg,0.79 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (100 mg, 0.66 mmol)were added to a degassed solution of the above compound (260 mg, 0.50mmol) in tetrahydrofuran (10 mL).

Bis(tri-tert-butylphosphine)palladium (15 mg, 0.03 mmol) and copper(I)iodide (10 mg, 0.05 mmol) were added; the reaction mixture was degassedagain and then stirred at ambient temperature over night under inertatmosphere. The reaction mixture was filtered through a pad of silicagel; the pad was washed with ethyl acetate (4×15 mL) and the combinedorganic filtrates were evaporated in vacuo. The residue was purified bycolumn chromatography (silica gel Fluka 60, hexanes/ethyl acetate 95:5)yielding methyl(Z)-[4-[3-(benzo[b]thiophen-2-yl)-3-[4-[4-(trifluoromethylphenyl)ethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate.

Yield: 210 mg (71%).

R_(F) (SiO₂, hexanes/ethyl acetate 80:20): 0.40.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.85-7.77 (m, 2H); 7.65-7.59(m, 4H); 7.50 (d, J=8.4 Hz, 2H); 7.43-7.36 (m, 3H); 7.26-7.24 (m, 2H,overlapped); 6.74 (bs, 1H); 6.64-6.63 (m, 2H); 6.42 (t, J=6.2 Hz, 1H);4.79 (d, J=6.2 Hz, 2H); 4.59 (s, 2H); 3.79 (s, 3H); 2.26 (s, 3H).

A solution of lithium hydroxide monohydrate (30 mg, 0.71 mmol) indistilled water (2 mL) was added to a solution of the above ester (210mg, 0.34 mmol) in tetrahydrofuran (5 mL) and methanol (2 ml) cooled to0° C. The solution was stirred for 2 h, acidified with 2 M hydrochloricacid to pH-6 and diluted with ethyl acetate (20 mL) and water (15 mL).The phases were separated and the aqueous phase was extracted with ethylacetate (3×15 mL).

The combined organic layers were washed with water (2×15 mL) and brine(2×15 mL), dried with anhydrous magnesium sulfate and evaporated invacuo. The residue was triturated with hexanes (2×15 mL) yielding thetitle acid as amorphous off-white powder.

Yield: 155 mg (76%).

M.p.: 162-172° C. (amorphous).

R_(F) (SiO₂, chloroform/methanol 90:10): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.85-7.78 (m, 2H); 7.65-7.58(m, 4H); 7.50 (d, J=8.4 Hz, 2H); 7.41-7.38 (m, 2H); 7.24 (s, 1H); 6.75(bs, 1H); 6.66 (bs, 2H); 6.41 (t, J=6.2 Hz, 1H); 4.78 (d, J=6.2 Hz, 2H);4.61 (s, 2H); 2.25 (s, 3H).

Example 79(E)-[7-[3-[4-[3-(Morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyaceticAcid

A mixture of 4-hydroxy-7-methoxybenzo[b]furan (2.0 g, 12.2 mmol;prepared according to Eur. J. Med. Chem. 1981, 16, 563), ethylbromoacetate (2.2 g, 13.2 mmol), potassium carbonate (2.0 g, 14.5 mmol)and 2-butanone (50 mL) was refluxed for 10 h, then filtered andevaporated in vacuo. The residue was purified by column chromatography(silica gel Fluka 60, chloroform) affording ethyl(7-methoxybenzo[b]furan-4-yloxy)acetate.

Yield: 2.77 g (91%).

R_(F) (SiO₂, benzene): 0.20.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.57 (d, J=1.8 Hz, 1H); 6.93(d, J=1.8 Hz, 1H); 6.66 (d, J=8.4 Hz, 1H); 6.48 (d, J=8.4 Hz, 1H); 4.70(s, 2H); 4.27 (q, J=7.1 Hz, 2H); 3.96 (s, 3H); 1.29 (t, J=7.1 Hz, 3H).

A solution of boron tribromide (5.50 g, 22 mmol) in dichloromethane (20mL) was added dropwise to a solution of the above ester (2.77 g, 11.1mmol) in dichloromethane (30 mL) at −40° C. and the mixture was stirredfor 3 h without cooling while the temperature reached 0° C. Water (3 mL)was added to the mixture the organic layer was evaporated in vacuo. Theobtained residue was purified by column chromatography (silica gel Fluka60, chloroform) affording ethyl (7-hydroxybenzo[b]furan-4-yloxy)acetate.

Yield: 2.15 g (82%).

R_(F) (SiO₂, ethyl acetate): 0.55.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.51 (d, J=1.8 Hz, 1H); 6.92(d, J=1.8 Hz, 1H); 6.67 (d, J=8.7 Hz, 1H); 6.41 (d, J=8.7 Hz, 1H); 4.70(s, 2H); 4.28 (q, J=7.1 Hz, 2H); 1.29 (t, J=7.1 Hz, 3H).

The above ester (0.83 g, 3.50 mmol),(Z)-3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)prop-2-en-1-ol (1.35 g,3.35 mmol) and triphenylphosphine (1.30 g, 5.00 mmol) were dissolved ina mixture of anhydrous toluene (30 mL) and tetrahydrofuran (3 mL). Themixture was cooled to 0° C., kept under nitrogen and diisopropylazodicarboxylate (1.10 g, 5.50 mmol) was added dropwise. The reactionmixture was stirred at 0° C. for 3 h and then left to stand at ambienttemperature for 3 days. The solvents were evaporated in vacuo and theresidue was submitted to column chromatography (silica gel Fluka 60,benzene) affording ethyl(Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yloxy]acetate.

Yield: 1.70 g (79%).

R_(F) (SiO₂, hexanes/ethyl acetate 5:1): 0.35.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.72 (d, J=8.4 Hz, 2H); 7.54(m, 3H); 7.34 (d, J=8.4 Hz, 2H); 6.92 (m, 3H); 6.57 (d, J=8.4 Hz, 1H);6.48 (t, J=6.6 Hz, 1H); 6.42 (d, J=8.4 Hz, 1H); 4.73 (d, J=6.6 Hz, 2H);4.69 (s, 2H); 4.27 (q, J=7.1 Hz, 2H); 1.29 (t, J=7.1 Hz, 3H).

N-Propargylmorpholine (0.64 g, 5.1 mmol) was added under nitrogenatmosphere to a degassed solution of ethyl(Z)-[7-[3-(4-iodophenyl)-3-(4-trifluoromethylphenyl)allyloxy]-benzo[b]furan-4-yl]oxyacetate(0.68 g, 1.09 mmol) in a mixture of tetrahydrofuran (20 mL) andtriethylamine (10 mL) The solution was cooled to 0° C.,tetrakis(triphenylphosphine)palladium (0.17 g, 0.147 mmol) and copper(I)iodide (0.03 g, 0.16 mmol) were added. The reaction mixture was stirredat ambient temperature for 120 h, diluted with benzene (100 mL),decanted and evaporated in vacuo. The residue was purified by columnchromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1)yielding ethyl(E)-[7-[3-[4-[3-(morpholin-4-yl)propynyl]phenyl]-3-(4-trifluoromethylphenyl)allyloxy]benzo[b]furan-4-yl]oxyacetate.

Yield: 0.60 g (89%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.70.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.53 (m, 3H); 7.46 (d, J=8.2Hz, 2H); 7.35 (d, J=8.2 Hz, 2H); 7.13 (d, J=8.2 Hz, 2H); 6.94 (d, J=2.1Hz, 1H); 6.56 (d, J=8.7 Hz, 1H); 6.47 (t, J=6.6 Hz, 1H); 6.42 (d, J=8.7Hz, 1H); 4.75 (d, J=6.6 Hz, 2H); 4.69 (s, 2H); 4.27 (q, J=7.1 Hz, 2H);3.79 (m, 4H); 3.54 (s, 2H); 2.67 (m, 4H); 1.29 (t, J=7.1 Hz, 3H).

The above ester (0.60 g, 1.02 mmol) was dissolved in ethanol (20 mL), asolution of lithium hydroxide monohydrate (0.085 g, 2.02 mmol) in water(2 mL) was added and the mixture was left to stand for 48 h. Thesolvents were evaporated in vacuo; the residue was treated with water(30 mL) and extracted with ether (2×10 mL) discarding the extracts. Theaqueous layer was acidified with acetic acid (1.0 mL) and extracted withdichloromethane (3×15 mL). The solvent was evaporated in vacuo and theresidue was triturated with ether (2×15 mL) yielding the title compoundas foam.

Yield: 0.35 g (61%).

R_(F) (SiO₂, chloroform/ethanol 5:1): 0.25.

¹H NMR spectrum (300 MHz, CDCl₃, δ_(H)): 7.53 (m, 3H); 7.42 (d, J=8.2Hz, 2H); 7.33 (d, J=8.2 Hz, 2H); 7.07 (d, J=8.2 Hz, 2H); 6.95 (d, J=2.1Hz, 1H); 6.49 (d+t, 2H); 6.38 (d, J=8.7 Hz, 1H); 4.69 (d, J=6.6 Hz, 2H);4.65 (s, 2H); 3.85 (m, 4H); 3.77 (s, 2H); 2.97 (m, 4H).

Pharmacological Methods

In Vitro Pparo Activation Activity

The PPAR transient transactivation assay is based on transienttransfection into human HEK293 cells of two plasmids encoding a chimerictest protein and a reporter protein respectively. The chimeric testprotein is a fusion of the DNA binding domain (DBD) from the yeast GAL4transcription factor to the ligand binding domain (LBD) of the humanPPAR proteins. The PPAR-LBD moiety harbored in addition to the ligandbinding pocket also the native activation domain (activating function2=AF2) allowing the fusion protein to function as a PPAR liganddependent transcription factor. The GAL4 DBD will direct the chimericprotein to bind only to Gal4 enhancers (of which none existed in HEK293cells). The reporter plasmid contained a Gal4 enhancer driving theexpression of the firefly luciferase protein. After transfection, HEK293cells expressed the GAL4-DBD-PPAR-LBD fusion protein. The fusion proteinwill in turn bind to the Gal4 enhancer controlling the luciferaseexpression, and do nothing in the absence of ligand. Upon addition tothe cells of a PPAR ligand luciferase protein will be produced inamounts corresponding to the activation of the PPAR protein. The amountof luciferase protein is measured by light emission after addition ofthe appropriate substrate.

Cell Culture and Transfection

HEK293 cells were grown in DMEM+10% FCS. Cells were seeded in 96-wellplates the day before transfection to give a confluency of 50-80% attransfection. A total of 0.8 μg DNA containing 0.64 μg pM1α/γLBD, 0.1 μgpCMVβGal, 0.08 μg pGL2(Gal4)₅ and 0.02 μg pADVANTAGE was transfected perwell using FuGene transfection reagent according to the manufacturersinstructions (Roche). Cells were allowed to express protein for 48 hfollowed by addition of compound.

Plasmids: Human PPAR-6 was obtained by PCR amplification using cDNAsynthesized by reverse transcription of mRNA from human liver, adiposetissue and plancenta respectively. Amplified cDNAs were cloned intopCR2.1 and sequenced. The ligand binding domain (LBD) of each PPARisoform was generated by PCR (PPARδ: aa 128—C-terminus) and fused to theDNA binding domain (DBD) of the yeast transcription factor GAL4 bysubcloning fragments in frame into the vector pM1 (Sadowski et al.(1992), Gene 118, 137) generating the plasmids pM1αLBD, pM1γLBD andpM1δ. Ensuing fusions were verified by sequencing. The reporter wasconstructed by inserting an oligonucleotide encoding five repeats of theGAL4 recognition sequence (Webster et al. (1988), Nucleic Acids Res. 16,8192) into the vector pGL2 promotor (Promega) generating the plasmidpGL2(GAL4)₅. pCMVPβGal was purchased from Clontech and pADVANTAGE waspurchased from Promega.

In Vitro Transactivation Assay

Compounds: All compounds were dissolved in DMSO and diluted 1:1000 uponaddition to the cells. Compounds were tested in quadruple inconcentrations ranging from 0.001 to 300 μM. Cells were treated withcompound for 24 h followed by luciferase assay. Each compound was testedin at least two separate experiments.Luciferase assay: Medium including test compound was aspirated and 100μl PBS incl. 1 mM Mg++ and Ca++ were added to each well. The luciferaseassay was performed using the LucLite kit according to themanufacturer's instructions (Packard Instruments). Light emission wasquantified by counting on a Packard LumiCounter. To measureβ-galactosidase activity 25 μl supernatant from each transfection lysatewas transferred to a new microplate. β-Galactosidase assays wereperformed in the microwell plates using a kit from Promega and read in aLabsystems Ascent Multiscan reader. The β-galactosidase data were usedto normalize (transfection efficiency, cell growth etc.) the luciferasedata.Statistical Methods

The activity of a compound is calculated as fold induction compared toan untreated sample. For each compound the efficacy (maximal activity)is given as a relative activity compared to Wy14,643 for PPARa,Rosiglitazone for PPARy and Carbacyclin for PPARS. The EC50 is theconcentration giving 50% of maximal observed activity. EC50 values werecalculated via non-linear regression using GraphPad PRISM 3.02 (GraphPadSoftware, San Diego, Ca). The results were expressed as means±SD.

While the invention has been described and illustrated with reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications, and substitutions can bemade therein without departing from the spirit and scope of the presentinvention. For example, effective dosages other than the preferreddosages as set forth herein may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated for PPAR-6mediated disease(s). Likewise, the specific pharmacological responsesobserved may vary according to and depending on the particular activecompound selected or whether there are present pharmaceutical carriers,as well as the type of formulation and mode of administration employed,and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention.

The invention claimed is:
 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

wherein

is a double bond, with either E or Z substitution; X₁ is C₁₋₆ alkyl substituted with morpholino; X₂ is phenylene; X₃ is phenyl substituted with one or more halogens; Ar is phenylene optionally substituted with methyl; Y₁ is O; Y₂ is O; Z is CH₂; R₁ is hydrogen; and R₂ is C₁₋₆-alkyl.
 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X₁ is morpholin-4-ylmethyl.
 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R₂ is methyl or ethyl.
 4. A pharmaceutically acceptable salt of a compound of formula (I):

wherein

is a double bond, with either E or Z substitution; X₁ is C₁₋₆ alkyl substituted with morpholino; X₂ is phenylene; X₃ is phenyl substituted with one or more halogens; Ar is phenylene optionally substituted with methyl; Y₁ is O; Y₂ is O; Z is CH₂; R₁ is hydrogen; and R₂ is C₁₋₆-alkyl.
 5. The pharmaceutically acceptable salt of claim 4, wherein X₁ is morpholin-4-ylmethyl.
 6. The pharmaceutically acceptable salt of claim 5, wherein R₂ is methyl or ethyl.
 7. The pharmaceutically acceptable salt of claim 1, wherein the pharmaceutically acceptable salt is an acid addition salt.
 8. The pharmaceutically acceptable salt of claim 1, wherein the pharmaceutically acceptable salt is an hydrochloric acid addition salt.
 9. A compound that is: methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate; or methyl (Z)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate; or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 1, wherein the compound is methyl (Z)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methylphenoxy]acetate, or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 1, wherein the compound is methyl (E)-[4-[3-(4-fluorophenyl)-3-[4-[3-(morpholin-4-yl)propynyl]phenyl]allyloxy]-2-methyl-phenoxy]acetate, or a pharmaceutically acceptable salt thereof. 